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

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

Tau-neurodegeneration mismatch reveals vulnerability and resilience to comorbidities in Alzheimer's continuum.

INTRODUCTION: Variability in relationship of tau-based neurofibrillary tangles (T) and neurodegeneration (N) in Alzheimer's disease (AD) arises from non-specific nature of N, modulated by non-AD co-pathologies, age-related changes, and resilience factors. METHODS: We used regional T-N residual patterns to partition 184 patients within the Alzheimer's continuum into data-driven groups. These were compared with groups from 159 non-AD (amyloid "negative") patients partitioned using cortical thickness, and groups in 98 patients with ante mortem MRI and post mortem tissue for measuring N and T, respectively. We applied the initial T-N residual model to classify 71 patients in an independent cohort into predefined groups. RESULTS: AD groups displayed spatial T-N mismatch patterns resembling neurodegeneration patterns in non-AD groups, similarly associated with non-AD factors and diverging cognitive outcomes. In the autopsy cohort, limbic T-N mismatch correlated with TDP-43 co-pathology. DISCUSSION: T-N mismatch may provide a personalized approach for determining non-AD factors associated with resilience/vulnerability in AD.

Medial Temporal Lobe Networks in Alzheimer's Disease: Structural and Molecular Vulnerabilities.

The medial temporal lobe (MTL) is connected to the rest of the brain through two main networks: the anterior-temporal (AT) and the posterior-medial (PM) systems. Given the crucial role of the MTL and networks in the physiopathology of Alzheimer's disease (AD), the present study aimed at (1) investigating whether MTL atrophy propagates specifically within the AT and PM networks, and (2) evaluating the vulnerability of these networks to AD proteinopathies. To do that, we used neuroimaging data acquired in human male and female in three distinct cohorts: (1) resting-state functional MRI (rs-fMRI) from the aging brain cohort (ABC) to define the AT and PM networks (n = 68); (2) longitudinal structural MRI from Alzheimer's disease neuroimaging initiative (ADNI)GO/2 to highlight structural covariance patterns (n = 349); and (3) positron emission tomography (PET) data from ADNI3 to evaluate the networks' vulnerability to amyloid and tau (n = 186). Our results suggest that the atrophy of distinct MTL subregions propagates within the AT and PM networks in a dissociable manner. Brodmann area (BA)35 structurally covaried within the AT network while the parahippocampal cortex (PHC) covaried within the PM network. In addition, these networks are differentially associated with relative tau and amyloid burden, with higher tau levels in AT than in PM and higher amyloid levels in PM than in AT. Our results also suggest differences in the relative burden of tau species. The current results provide further support for the notion that two distinct MTL networks display differential alterations in the context of AD. These findings have important implications for disease spread and the cognitive manifestations of AD.SIGNIFICANCE STATEMENT The current study provides further support for the notion that two distinct medial temporal lobe (MTL) networks, i.e., anterior-temporal (AT) and the posterior-medial (PM), display differential alterations in the context of Alzheimer's disease (AD). Importantly, neurodegeneration appears to occur within these networks in a dissociable manner marked by their covariance patterns. In addition, the AT and PM networks are also differentially associated with relative tau and amyloid burden, and perhaps differences in the relative burden of tau species [e.g., neurofibriliary tangles (NFTs) vs tau in neuritic plaques]. These findings, in the context of a growing literature consistent with the present results, have important implications for disease spread and the cognitive manifestations of AD in light of the differential cognitive processes ascribed to them.

Respective influence of beta-amyloid and APOE ε4 genotype on medial temporal lobe subregions in cognitively unimpaired older adults.

Medial temporal lobe (MTL) subregions are differentially affected in Alzheimer's disease (AD), with a specific involvement of the entorhinal cortex (ERC), perirhinal cortex and hippocampal cornu ammonis (CA)1. While amyloid (Aß) and APOEε4 are respectively the first molecular change and the main genetic risk factor in AD, their links with MTL atrophy remain relatively unclear. Our aim was to uncover these effects using baseline data from 130 participants included in the Age-Well study, for whom ultra-high-resolution structural MRI, amyloid-PET and APOEε4 genotype were available. No volume differences were observed between Aß + (n = 24) and Aß- (n = 103), nor between APOE4+ (n = 35) and APOE4- (n = 95) participants. However, our analyses showed that both Aß and APOEε4 status interacted with age on CA1, which is known to be specifically atrophied in early AD. In addition, APOEε4 status moderated the effects of age on other subregions (subiculum, ERC), suggesting a more important contribution of APOEε4 than Aß to MTL atrophy in cognitively unimpaired population. These results are crucial to develop MRI-based biomarkers to detect early AD.

Longitudinal Changes in Hippocampal Network Connectivity in Alzheimer's Disease.

OBJECTIVE: The hippocampus is connected to 2 distinct cortical brain networks, the posterior-medial and the anterior-temporal networks, involving different medial temporal lobe (MTL) subregions. The aim of this study was to assess the functional alterations of these 2 networks, their changes over time, and links to cognition in Alzheimer's disease. METHODS: We assessed MTL connectivity in 53 amyloid-ß-positive patients with mild cognitive impairment and AD dementia and 68 healthy elderly controls, using resting-state functional magnetic resonance imaging, cross-sectionally and longitudinally. First, we compared the functional connectivity of the posterior-medial and anterior-temporal networks within the control group to highlight their specificities. Second, we compared the connectivity of these networks between groups, and between baseline and 18-month follow-up in patients. Third, we assessed the association in the connectivity changes between the 2 networks, and with cognitive performance. RESULTS: We found decreased connectivity in patients specifically between the hippocampus and the posterior-medial network, together with increased connectivity between several MTL subregions and the anterior-temporal network. Moreover, changes in the posterior-medial and anterior-temporal networks were interrelated such that decreased MTL-posterior-medial connectivity was associated with increased MTL-anterior-temporal connectivity. Finally, both MTL-posterior-medial decrease and MTL-anterior-temporal increase predicted cognitive decline. INTERPRETATION: Our findings demonstrate that longitudinal connectivity changes in the posterior-medial and anterior-temporal hippocampal networks are linked together and that they both contribute to cognitive decline in Alzheimer's disease. These results shed light on the critical role of the posterior-medial and anterior-temporal networks in Alzheimer's disease pathophysiology and clinical symptoms. ANN NEUROL 2021;90:391-406.

Tau-Atrophy Variability Reveals Phenotypic Heterogeneity in Alzheimer's Disease.

OBJECTIVE: Tau neurofibrillary tangles (T) are the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in Alzheimer's disease (AD). However, there is substantial variability in the T-N relationship - manifested in higher or lower atrophy than expected for level of tau in a given brain region. The goal of this study was to determine if region-based quantitation of this variability allows for identification of underlying modulatory factors, including polypathology. METHODS: Cortical thickness (N) and 18 F-Flortaucipir SUVR (T) were computed in 104 gray matter regions from a cohort of cognitively-impaired, amyloid-positive (A+) individuals. Region-specific residuals from a robust linear fit between SUVR and cortical thickness were computed as a surrogate for T-N mismatch. A summary T-N mismatch metric defined using residuals were correlated with demographic and imaging-based modulatory factors, and to partition the cohort into data-driven subgroups. RESULTS: The summary T-N mismatch metric correlated with underlying factors such as age and burden of white matter hyperintensity lesions. Data-driven subgroups based on clustering of residuals appear to represent different biologically relevant phenotypes, with groups showing distinct spatial patterns of higher or lower atrophy than expected. INTERPRETATION: These data support the notion that a measure of deviation from a normative relationship between tau burden and neurodegeneration across brain regions in individuals on the AD continuum captures variability due to multiple underlying factors, and can reveal phenotypes, which if validated, may help identify possible contributors to neurodegeneration in addition to tau, which may ultimately be useful for cohort selection in clinical trials. ANN NEUROL 2021;90:751-762.

Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe.

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.

White matter hyperintensity topography in Alzheimer's disease and links to cognition.

INTRODUCTION: White matter hyperintensities (WMH) are often described in Alzheimer's disease (AD), but their topography and specific relationships with cognition remain unclear. METHODS: Regional WMH were estimated in 54 cognitively impaired amyloid beta-positive AD (Aßpos-AD), compared to 40 cognitively unimpaired amyloid beta-negative older controls (Aßneg-controls) matched for vascular risk factors. The cross-sectional association between regional WMH volume and cognition was assessed within each group, controlling for cerebral amyloid burden, global cortical atrophy, and hippocampal atrophy. RESULTS: WMH volume was larger in Aßpos-AD compared to Aßneg-controls in all regions, with the greatest changes in the splenium of the corpus callosum (S-CC). In Aßpos-AD patients, larger total and regional WMH volume, especially in the S-CC, was strongly associated with decreased cognition. DISCUSSION: WMH specifically contribute to lower cognition in AD, independently from amyloid deposition and atrophy. This study emphasizes the clinical relevance of WMH in AD, especially posterior WMH, and most notably S-CC WMH.

Hippocampal subfield volumetry from structural isotropic 1 mm3 MRI scans: A note of caution.

Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images.

Characterization of hippocampal subfields using ex vivo MRI and histology data: Lessons for in vivo segmentation.

Hippocampal subfield segmentation on in vivo MRI is of great interest for cognition, aging, and disease research. Extant subfield segmentation protocols have been based on neuroanatomical references, but these references often give limited information on anatomical variability. Moreover, there is generally a mismatch between the orientation of the histological sections and the often anisotropic coronal sections on in vivo MRI. To address these issues, we provide a detailed description of hippocampal anatomy using a postmortem dataset containing nine specimens of subjects with and without dementia, which underwent a 9.4 T MRI and histological processing. Postmortem MRI matched the typical orientation of in vivo images and segmentations were generated in MRI space, based on the registered annotated histological sections. We focus on the following topics: the order of appearance of subfields, the location of subfields relative to macroanatomical features, the location of subfields in the uncus and tail and the composition of the dark band, a hypointense layer visible in T2-weighted MRI. Our main findings are that: (a) there is a consistent order of appearance of subfields in the hippocampal head, (b) the composition of subfields is not consistent in the anterior uncus, but more consistent in the posterior uncus, (c) the dark band consists only of the CA-stratum lacunosum moleculare, not the strata moleculare of the dentate gyrus, (d) the subiculum/CA1 border is located at the middle of the width of the hippocampus in the body in coronal plane, but moves in a medial direction from anterior to posterior, and (e) the variable location and composition of subfields in the hippocampal tail can be brought back to a body-like appearance when reslicing the MRI scan following the curvature of the tail. Our findings and this publicly available dataset will hopefully improve anatomical accuracy of future hippocampal subfield segmentation protocols.

Longitudinal atrophy in early Braak regions in preclinical Alzheimer's disease.

A major focus of Alzheimer's disease (AD) research has been finding sensitive outcome measures to disease progression in preclinical AD, as intervention studies begin to target this population. We hypothesize that tailored measures of longitudinal change of the medial temporal lobe (MTL) subregions (the sites of earliest cortical tangle pathology) are more sensitive to disease progression in preclinical AD compared to standard cognitive and plasma NfL measures. Longitudinal T1-weighted MRI of 337 participants were included, divided into amyloid-ß negative (Aß-) controls, cerebral spinal fluid p-tau positive (T+) and negative (T-) preclinical AD (Aß+ controls), and early prodromal AD. Anterior/posterior hippocampus, entorhinal cortex, Brodmann areas (BA) 35 and 36, and parahippocampal cortex were segmented in baseline MRI using a novel pipeline. Unbiased change rates of subregions were estimated using MRI scans within a 2-year-follow-up period. Experimental results showed that longitudinal atrophy rates of all MTL subregions were significantly higher for T+ preclinical AD and early prodromal AD than controls, but not for T- preclinical AD. Posterior hippocampus and BA35 demonstrated the largest group differences among hippocampus and MTL cortex respectively. None of the cross-sectional MTL measures, longitudinal cognitive measures (PACC, ADAS-Cog) and cross-sectional or longitudinal plasma NfL reached significance in preclinical AD. In conclusion, longitudinal atrophy measurements reflect active neurodegeneration and thus are more directly linked to active disease progression than cross-sectional measurements. Moreover, accelerated atrophy in preclinical AD seems to occur only in the presence of concomitant tau pathology. The proposed longitudinal measurements may serve as efficient outcome measures in clinical trials.

Contribution of mixed pathology to medial temporal lobe atrophy in Alzheimer's disease.

INTRODUCTION: It is unclear how different proteinopathies (tau, transactive response DNA-binding protein 43 [TDP-43], amyloid ß [Aß], and α-synuclein) contribute to atrophy within medial temporal lobe (MTL) subregions in Alzheimer's disease (AD). METHODS: We utilized antemortem structural magnetic resonance imaging (MRI) data to measure MTL substructures and examined the relative contribution of tau, TDP-43, Aß, and α-synuclein measured in post-mortem tissue from 92 individuals with intermediate to high AD neuropathology. Receiver-operating characteristic (ROC) curves were analyzed for each subregion in order to discriminate TDP-43-negative and TDP-43-positive patients. RESULTS: TDP-43 was strongly associated with anterior MTL regions, whereas tau was relatively more associated with the posterior hippocampus. Among the MTL regions, the anterior hippocampus showed the highest area under the ROC curve (AUC). DISCUSSION: We found specific contributions of different pathologies on MTL substructure in this population with AD neuropathology. The anterior hippocampus may be a relevant region to detect concomitant TDP-43 pathology in the MTL of patients with AD.

Hippocampal subfields alterations in adolescents with post-traumatic stress disorder.

Reexperiencing symptoms in adolescent Post-Traumatic Stress Disorder (PTSD) are characterized by the apparition of vivid intrusive images of the traumatic event. The emergence of these intrusions is thought to be related to a deficiency in context processing and could then be related to hippocampal alterations. The hippocampus is a complex structure which can be divided into several subfields, namely, the Cornu Ammonis (CA1, CA2, and CA3), the subiculum, and the dentate gyrus (DG). As each subfield presents different histological characteristics and functions, it appears more relevant to consider hippocampal subfields, instead of only assessing the whole hippocampus, to understand the neurobiology of PTSD. Hence, this study presents the first investigation of structural alterations within hippocampal subfields and their links to reexperiencing symptoms in adolescent PTSD. Hippocampal subfields were manually delineated on high-resolution MRI images in 15 adolescents (13-18 years old) with PTSD and 24 age-matched healthy controls. The volume of the region CA2-3/DG region was significantly smaller in the PTSD group compared to controls in both hemispheres. No other significant difference was found for other subfields. Moreover, the volume of the left CA2-3/DG was negatively correlated with the intrusion score (as measured by the Impact of Events Scale-Revised) in the PTSD group. To conclude, an alteration in the hippocampal subregion CA2-3/DG, known to resolve interferences between new and similar stored memories, could participate in the apparition of intrusive trauma memories in adolescents with PTSD.

Automated segmentation of medial temporal lobe subregions on in vivo T1-weighted MRI in early stages of Alzheimer's disease.

Medial temporal lobe (MTL) substructures are the earliest regions affected by neurofibrillary tangle pathology-and thus are promising biomarkers for Alzheimer's disease (AD). However, automatic segmentation of the MTL using only T1-weighted (T1w) magnetic resonance imaging (MRI) is challenging due to the large anatomical variability of the MTL cortex and the confound of the dura mater, which is commonly segmented as gray matter by state-of-the-art algorithms because they have similar intensity in T1w MRI. To address these challenges, we developed a novel atlas set, consisting of 15 cognitively normal older adults and 14 patients with mild cognitive impairment with a label explicitly assigned to the dura, that can be used by the multiatlas automated pipeline (Automatic Segmentation of Hippocampal Subfields [ASHS-T1]) for the segmentation of MTL subregions, including anterior/posterior hippocampus, entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36, and parahippocampal cortex on T1w MRI. Cross-validation experiments indicated good segmentation accuracy of ASHS-T1 and that the dura can be reliably separated from the cortex (6.5% mislabeled as gray matter). Conversely, FreeSurfer segmented majority of the dura mater (62.4%) as gray matter and the degree of dura mislabeling decreased with increasing disease severity. To evaluate its clinical utility, we applied the pipeline to T1w images of 663 ADNI subjects and significant volume/thickness loss is observed in BA35, ERC, and posterior hippocampus in early prodromal AD and all subregions at later stages. As such, the publicly available new atlas and ASHS-T1 could have important utility in the early diagnosis and monitoring of AD and enhancing brain-behavior studies of these regions.

A harmonized segmentation protocol for hippocampal and parahippocampal subregions: Why do we need one and what are the key goals?

The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies. © 2016 Wiley Periodicals, Inc.

Intrinsic connectivity of hippocampal subfields in normal elderly and mild cognitive impairment patients.

Hippocampal connectivity has been widely described but connectivity specificities of hippocampal subfields and their changes in early AD are poorly known. The aim of this study was to highlight hippocampal subfield networks in healthy elderly (HE) and their changes in amnestic patients with mild cognitive impairment (aMCI). Thirty-six HE and 27 aMCI patients underwent resting-state functional MRI scans. Specific intrinsic connectivity of bilateral CA1, SUB (subiculum), and CA2/3/4/DG was identified in HE (using seeds derived from manually delineation on high-resolution scans) and compared between HE and aMCI. Compared to the other subfields, CA1 was more strongly connected to the amygdala and occipital regions, CA2/3/4/DG to the left anterior cingulate cortex, temporal, and occipital regions, and SUB to the angular, precuneus, putamen, posterior cingulate, and frontal regions. aMCI patients showed reduced connectivity within the SUB network (with frontal and posterior cingulate regions). Our study highlighted for the first time three specific and distinct hippocampal subfield functional networks in HE, and their alterations in aMCI. These findings are important to understand AD specificities in both cognitive deficits and lesion topography, given the role of functional connectivity in these processes. Hum Brain Mapp 38:4922-4932, 2017. © 2017 Wiley Periodicals, Inc.

Differential associations of age with volume and microstructure of hippocampal subfields in healthy older adults.

Hippocampal atrophy in advanced healthy aging has frequently been reported. However, the vulnerability of different hippocampal subfields to age-related atrophy is still a source of debate. Moreover, the association of age with the microstructural integrity of subfields is largely unknown. In this study, we investigated the associations between age and volume as well as microstructural integrity of hippocampal subfields using a three-dimensional (3D) surface mapping approach. Forty-three healthy older adults spanning the age range from 60 to 85 years underwent T1-weighted and diffusion-tensor imaging. Analyses demonstrated an association of age with hippocampal volume predominantly in the most anterior part of the hippocampal head, mainly corresponding to the subiculum. In contrast, the association of age with hippocampal microstructural integrity was mainly confined to regions located in the hippocampal body and tail, corresponding to the subiculum and CA1. Results indicate that age-related volumetric and microstructural alterations within hippocampal subfields provide complementary information and reflect different age-related processes. Potential mechanisms underlying the differential associations of age with volume and microstructure of hippocampal subfields are discussed.

Effects of age and Alzheimer's disease on hippocampal subfields: comparison between manual and FreeSurfer volumetry.

Growing interest has developed in hippocampal subfield volumetry over the past few years and an increasing number of studies use the automatic segmentation algorithm implemented in FreeSurfer. However, this approach has not been validated on standard resolution T1-weighted magnetic resonance (MR) as used in most studies. We aimed at comparing hippocampal subfield segmentation using FreeSurfer on standard T1-weighted images versus manual delineation on dedicated high-resolution hippocampal scans. Hippocampal subfields were segmented in 133 individuals including 98 cognitively normal controls aged 19-84 years, 17 mild cognitive impairment and 18 Alzheimer's disease (AD) patients using both methods. Intraclass correlation coefficients (ICC) and Bland-Altman plots were computed to assess the consistency between both methods, and the effects of age and diagnosis were assessed from both measures. Low to moderate ICC (0.31-0.74) were found for the subiculum and other subfields as well as for the whole hippocampus, and the correlations were very low for cornu ammonis (CA)1 (<0.1). FreeSurfer CA1 volume estimates were found to be much lower than those obtained from manual segmentation, and this bias was proportional to the volume of this structure so that no effect of age or AD could be detected on FreeSurfer CA1 volumes. This study points to the differences in the anatomic definition of the subfields between FreeSurfer and manual delineation, especially for CA1, and provides clue for improvement of this automatic technique for potential clinical application on standard T1-weighted MR.

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

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the 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 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 (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.

Baseline structural MRI and plasma biomarkers predict longitudinal structural atrophy and cognitive decline in early Alzheimer's disease.

BACKGROUND: Crucial to the success of clinical trials targeting early Alzheimer's disease (AD) is recruiting participants who are more likely to progress over the course of the trials. We hypothesize that a combination of plasma and structural MRI biomarkers, which are less costly and non-invasive, is predictive of longitudinal progression measured by atrophy and cognitive decline in early AD, providing a practical alternative to PET or cerebrospinal fluid biomarkers. METHODS: Longitudinal T1-weighted MRI, cognitive (memory-related test scores and clinical dementia rating scale), and plasma measurements of 245 cognitively normal (CN) and 361 mild cognitive impairment (MCI) patients from ADNI were included. Subjects were further divided into ß-amyloid positive/negative (Aß+/Aß-)] subgroups. Baseline plasma (p-tau181 and neurofilament light chain) and MRI-based structural medial temporal lobe subregional measurements and their association with longitudinal measures of atrophy and cognitive decline were tested using stepwise linear mixed effect modeling in CN and MCI, as well as separately in the Aß+/Aß- subgroups. Receiver operating characteristic (ROC) analyses were performed to investigate the discriminative power of each model in separating fast and slow progressors (first and last terciles) of each longitudinal measurement. RESULTS: A total of 245 CN (35.0% Aß+) and 361 MCI (53.2% Aß+) participants were included. In the CN and MCI groups, both baseline plasma and structural MRI biomarkers were included in most models. These relationships were maintained when limited to the Aß+ and Aß- subgroups, including Aß- CN (normal aging). ROC analyses demonstrated reliable discriminative power in identifying fast from slow progressors in MCI [area under the curve (AUC): 0.78-0.93] and more modestly in CN (0.65-0.73). CONCLUSIONS: The present data support the notion that plasma and MRI biomarkers, which are relatively easy to obtain, provide a prediction for the rate of future cognitive and neurodegenerative progression that may be particularly useful in clinical trial stratification and prognosis. Additionally, the effect in Aß- CN indicates the potential use of these biomarkers in predicting a normal age-related decline.