Reduced cortical thickness in hippocampal subregions among cognitively normal apolipoprotein E e4 carriers

Structural brain changes appear years before the onset of Alzheimer's disease, the leading cause of dementia late in life. Determining risk factors for such presymptomatic brain changes may assist in identifying candidates for future prevention treatment trials. In addition to the e4 allele of the apolipoprotein E gene (APOE-4), the major known genetic risk factor, a family history of Alzheimer's disease also increases the risk to develop the disease, reflecting yet unidentified genetic and, perhaps, nongenetic risks. The authors investigated the influence of APOE-4 genotype and family history risks on cortical thickness in medial temporal lobe subregions among volunteers without cognitive impairment. High-resolution magnetic resonance imaging (MRI) and a cortical unfolding method were performed on 26 subjects (APOE-4 carriers: N=13; noncarriers: N=13) with at least one first-degree relative with Alzheimer's disease and 25 subjects (APOE-4 carriers: N=12; noncarriers: N=13) without this risk factor. All subjects (mean age: 62.3 years [SD=10.7]; range=38-86 years) were cognitively healthy. Family history of Alzheimer's disease and APOE-4 status were associated with a thinner cortex in the entorhinal region, subiculum, and adjacent medial temporal lobe subfields. Although these associations were additive, family history of Alzheimer's disease explained a greater proportion of the unique variance in cortical thickness than APOE-4 carrier status. APOE-4 carrier status and family history of Alzheimer's disease are independently associated with and contribute additively to hippocampal cortical thinning.

Many studies have focused on the function of hippocampal region CA1 as a critical site for associative memory, but much less is known about changes in the afferents to CA1. Here we report the activity of multiple single neurons from perirhinal and entorhinal cortex and from dentate gyrus during trace eyeblink conditioning as well as consolidated recall, and in pseudo-conditioned control rabbits. We also report an analysis of theta activity filtered from the local field potential (LFP). Our results show early associative changes in single-neuron firing rate as well as theta oscillations in lateral entorhinal cortex (EC) and dentate gyrus (DG), and increases in the number of responsive neurons in perirhinal cortex. In both EC and DG, a subset of neurons from conditioned animals exhibited an elevated baseline firing rate and large responses to the conditioned stimulus and trace period. A similar population of cells has been seen in DG and in medial, but not lateral, EC during spatial tasks, suggesting that lateral EC contains cells responsive to a temporal associative task. In contrast to recent studies in our laboratory that found significant CA1 contributions to long-term memory, the activity profiles of neurons within EC and DG were similar for conditioned and pseudoconditioned rabbits during post-consolidation sessions. Collectively these results demonstrate that individual subregions of medial temporal lobe differentially support new and remotely acquired memories. Neuron firing profiles were similar on training trials when conditioned responses were and were not exhibited, demonstrating that these temporal lobe regions represent the CS-US association and do not control the behavioral response. The analysis of theta activity revealed that theta power was modulated by the conditioning stimuli in both the conditioned and pseudoconditioned groups and that although both groups exhibited a resetting of phase to the corneal airpuff, only the conditioned group exhibited a resetting of phase to the whisker conditioned stimulus.

The human entorhinal-hippocampal circuitry is characterized by an information-specific functional organization where two routes, that are preferentially connected to the parahippocampal cortex or the perirhinal and retrosplenial cortices, divide the entorhinal cortex as well as hippocampal subiculum and CA1 subregions.

BackgroundSleep‐disordered breathing (SDB) has been associated to greater amyloid deposition and dementia risk. However, the pattern of SDB‐associated structural brain changes is unclear, especially within the medial temporal lobe (MTL). We investigated the associations between SDB severity and the volume of MTL subregions, and hypothesized that SDB would be associated with atrophy in regions early affected by Alzheimer’s disease (AD) pathology and/or sensitive to hypoxia (i.e., the perirhinal and entorhinal cortices, and CA1 hippocampal subfield), particularly in amyloid‐positive participants.MethodWe included 120 cognitively unimpaired older participants from the Age‐Well randomized controlled trial (mean age=69 ± 3,8 years; 25 Aβ+ and 95 Aβ‐ participants). They underwent a structural MRI, including a high‐resolution T2‐weighted sequence of the MTL (0.4x0.4x2.5mm3), a Florbetapir‐PET scan to measure amyloid deposition, as well as a polysomnography. The ASHS (Automatic Segmentation of Hippocampal Subfields) software was used to segment the entorhinal, perirhinal, and parahippocampal cortices, as well as hippocampal subfields (i.e., the subiculum, CA1, CA2‐3, the dentate gyrus, their sum representing total hippocampal volume) on high‐resolution MRI sequences. Bilateral volumes normalized to the total intracranial volume were used in statistical analyses. We performed linear regressions with the volume of each MTL subregion as dependent variables, the apnea‐hypopnea index (AHI, reflecting SDB severity) and amyloid status as independent variables, and age, sex, education and the ApoE4 status as covariates.ResultWe found significant interactions between the AHI and amyloid status on the volumes of the entorhinal cortex (p<0.001), whole hippocampus (p<0.001), subiculum (p<0.001), CA1 (p=0.003) and dentate gyrus (p=0.007), such that the AHI significantly predicted the volume of these MTL subregions only in amyloid‐positive participants (Figure 1).ConclusionUntreated SDB has been previously associated with increased amyloid deposition, even in the absence of cognitive or sleep symptoms. Our data complement these findings by showing that once amyloid deposition reaches positivity, greater SDB severity is related to neurodegeneration in several MTL subregions, including the entorhinal cortex and hippocampus. Thus, the presence of SDB in cognitively unimpaired older adults who are engaged in the Alzheimer’s continuum may increase the risk of developing memory impairment over time.

BackgroundAccumulation of tau neurofibrillary tangles (NFT) in the medial temporal lobe (MTL) is an early pathological change associated with neurodegeneration in Alzheimer’s Disease (AD). Current understanding of the spread of NFTs within the MTL is based on 2‐D histological sections sampled at sparse locations. Here, using human MTL specimens from donors with diagnoses spanning the AD continuum, we examine 3‐D quantitative maps of NFT burden derived from serial histology leveraging a high‐resolution, ex vivo MRI atlas, thus enabling more granular analyses.MethodWe combined ex vivo MRI scans (0.2×0.2×0.2mm3, 9.4T) of 55 MTL specimens using a customized registration approach to construct a 3‐D atlas (Ravikumar et al., Acta Neuropathol Comm, 2021). MTL subregions in the atlas were labelled based on cytoarchitecture using serial Nissl histology (n = 17) (Fig.1). For 25 specimens with a primary diagnosis of AD or primary age‐related tauopathy (78.6±10.9 years; 16M/9F), quantitative NFT burden maps were derived from serial anti‐tau immunohistochemistry histology and registered to the atlas for group‐level analysis (Yushkevich et al., Brain, 2021). For quantitative comparisons, we computed the mean NFT burden and cortical thickness within each subregion.ResultFig.2A shows average and summary frequency maps of NFT burden, computed separately for specimens with a low Braak stage (Braak0‐II; n = 11) and high Braak stage (BraakIV‐VI), that reveal a clear anterior‐to‐posterior gradient in NFT burden. At low Braak stages, we observe high levels of NFT burden in cornu ammonis (CA)1, entorhinal cortex (EC), and Brodmann area 35 (BA35;≈transentorhinal region), particularly in the outer cortical layers. CA1 and EC also show higher NFT burden relative to BA35 (Fig.2C). At high Braak stages, overall NFT burden is visibly higher and more widespread, with significant increases found across almost all subregions (Fig.2B). Moreover, significant correlations between NFT burden and cortical thinning were found in the perforant pathway (PP; molecular layer of the subiculum), dentate gyrus, EC and Areas TE, TF and TH (Fig.3).ConclusionBuilding on earlier work, we provide a detailed characterization of the distribution of NFT burden in the MTL. Our findings of specific subregional involvement of early NFT pathology can help inform the development of improved in vivo neuroimaging biomarkers

Although the medial temporal lobe (MTL) is known to be essential for episodic encoding, the contributions of individual MTL subregions remain unclear. Data from recognition memory studies have provided evidence that the hippocampus supports relational encoding important for later episodic recollection, whereas the perirhinal cortex has been linked with encoding that supports later item familiarity. However, extant data also strongly implicate the perirhinal cortex in object processing and encoding, suggesting that perirhinal processes may contribute to later episodic recollection of object source details. To investigate this possibility, encoding activation in MTL subregions was analyzed on the basis of subsequent memory outcome while participants processed novel scenes paired with 1 of 6 repeating objects. Specifically, encoding activation correlating with later successful scene recognition memory was evaluated against that of source recollection for the object paired with the scene during encoding. In contrast to studies reporting a link between perirhinal cortex and item familiarity, it was found that encoding activation in the right perirhinal cortex correlates with successful recollection of the paired object. Furthermore, other MTL subregions also exhibited content-specific source encoding patterns of activation, suggesting that MTL subsequent memory effects are sensitive to stimulus category.

BackgroundAPOE‐ε4 and ABCA7‐80 (rs115550680) are two prominent genetic risk factors for Alzheimer’s disease (AD). While APOE‐ε4 is the most common genetic risk factor for AD in people of European ancestry, ABCA7‐80 is linked to late‐onset AD in individuals of African ancestry. The medial temporal lobe (MTL), an early locus of AD‐related pathology, is critical for memory and attention. Understanding genotype‐specific alterations in MTL connectivity with cortical regions is crucial for identifying early biomarkers of AD in African‐ancestry populations. To investigate MTL‐cortical connectivity in cognitively unimpaired older adults with African ancestry carrying the high‐risk ABCA7‐80 and APOE‐ε4 alleles.MethodParticipants (N =146; Mean Age = 69.71±6.29; 110 women) were drawn from the Aging and Health Alliance study at Rutgers‐Newark. Genetic status for APOE‐ε4 and ABCA7‐80 was determined using saliva‐based genotyping. Resting‐state functional MRI (rs‐fMRI) was used to perform seed‐based connectivity analyses, focusing on MTL and hippocampal subregions (Subiculum, Cornu Ammonis 1 (CA1), Dentate Gyrus (DG)/CA3, Parahippocampal Cortex, Perirhinal Cortex, Anterolateral Entorhinal Cortex, and Posteromedial Entorhinal Cortex) and their cortical targets. Group differences in connectivity were assessed using t‐statistic maps, with age, sex, and education as covariates, and significance was determined via Threshold‐Free Cluster Enhancement (TFCE) correction (p < .05).ResultABCA7‐80 carriers exhibited significantly reduced functional connectivity between the subiculum and the supramarginal gyrus, and between the DG/CA3 and the superior parietal lobule, compared to APOE‐ε4 carriers (TFCE corrected p < .05). These disruptions suggest that ABCA7‐80 carriers may exhibit early alterations in memory consolidation and attention integration networks, potentially increasing their risk of cognitive decline.ConclusionAPOE‐ε4 and ABCA7‐80 differentially shape MTL‐parietal networks in preclinical stages of AD. The observed decrease in connectivity in ABCA7‐80 carriers may reflect early dysfunction in neural networks involved in memory and attention. ABCA7‐80 may therefore serve as an early marker of neural disruption in older adults of African ancestry, providing valuable insights for genotype‐targeted interventions.

Within the rat medial temporal lobe, transient modulations of neural cell adhesion molecule (NCAM) polysialylation have been observed to follow spatial learning. These have been attributed to neuroplastic events associated with the processing of information destined for long term memory consolidation. To determine if similar events are associated with avoidance learning, we investigated change in polysialylated cell number in the entorhinal, perirhinal, and piriform cortex, following acquisition of a passive avoidance task in the rat. Direct quantification of polysialylated neurons in layer II of these cortical regions revealed a significant increase in polysialylated cell frequency at 12 h following passive avoidance training. Unlike spatial learning, the increased expression of polysialylated neurons persisted for up to 24-48 h following training. In the more dorsal aspect of the perirhinal/entorhinal cortex, this increase was found to be specific to learning, as it was not observed in animals rendered amnesic with scopolamine. By contrast, change in polysialylated cell frequency in the ventral aspect of the medial temporal lobe was only partially reduced by amnesic doses of scopolamine. The persisting activation of NCAM polysialylation in the more dorsal aspects of the perirhinal and entorhinal cortex is suggested to reflect the need for more extensive synaptic alterations, as compared to those required for the consolidation of spatial learning. Moreover, the neuroplastic modulations observed in the more ventral regions of the entorhinal and perirhinal cortex appear to be a unique aspect of avoidance conditioning that reflects the activation of alternative learning strategies associated with motivational and/or contextual parameters of the task.

Objective: Evaluation of interrater reliability for manual segmentation of brain structures that are affected first by neurofibrillary tau pathology in Alzheimer's disease. Method: Medial perirhinal cortex, lateral perirhinal cortex, and entorhinal cortex were manually segmented by two raters on structural magnetic resonance images of 44 adults (20 men; mean age = 69.2 ± 10.4 years). Intraclass correlation coefficients (ICC) of cortical thickness and volumes were calculated. Results: Very high ICC values of manual segmentation for the cortical thickness of all regions (0.953-0.986) and consistently lower ICC values for volume estimates of the medial and lateral perirhinal cortex (0.705-0.874). Conclusions: The applied manual segmentation protocol allows different raters to achieve remarkably similar cortical thickness estimates for regions of the parahippocampal gyrus. In addition, the results suggest a preference for cortical thickness over volume as a reliable measure of atrophy, especially for regions affected by collateral sulcus variability (i.e., medial and lateral perirhinal cortex). The results provide a basis for future automated segmentation and collection of normative data.

The medial temporal lobe (MTL) is involved in mnemonic processing. The perirhinal cortex (PRC) plays a role in object recognition memory, while the hippocampus is required for certain forms of spatial memory and episodic memory. The lateral entorhinal cortex (LEC) receives direct projections from PRC and is one of the two major cortical inputs to the hippocampus. The transformations that occur between PRC and LEC neural representations are not well understood. Here, we show that PRC and LEC had similarly high proportions of neurons with object-related activity (PRC 52/94; LEC 72/153), as expected from their locations in the "what" pathway into the hippocampus. However, LEC unit activity showed more spatial stability than PRC unit activity. A minority of LEC neurons showed stable spatial firing fields away from objects; these firing fields strongly resembled hippocampal place fields. None of the PRC neurons showed this place-like firing. None of the PRC or LEC neurons demonstrated the high firing rates associated with interneurons in hippocampus or medial entorhinal cortex, further dissociating this information processing stream from the path-integration based, movement-related processing of the medial entorhinal cortex and hippocampus. These results provide evidence for nonspatial information processing in the PRC-LEC pathway, as well as showing a functional dissociation between PRC and LEC, with more purely nonspatial representations in PRC and combined spatial-nonspatial representations in LEC.

Using functional magnetic resonance imaging, the current study explored the differential mnemonic contributions of the hippocampus and surrounding medial temporal lobe (MTL) cortices to explicit recognition memory and configural learning. Using a task that required processing of repeated and novel visuospatial contexts across multiple trials, we examined MTL activation in relation to 3 forms of learning in a single paradigm: 1) context-independent procedural learning, 2) context-dependent configural learning, and 3) explicit recognition memory. Activations in hippocampus and parahippocampal cortex were associated with explicit memory, differentiating between subsequently remembered and forgotten repeated contexts, but were unrelated to context-dependent configural learning. Activations in regions of perirhinal and entorhinal cortex were associated with configural learning of repeated contexts independent from explicit memory for those contexts. Procedural learning was unrelated to activation in any MTL region. The time course of activation across learning further differed in MTL subregions with MTL cortex demonstrating repetition-related decreases and hippocampus repetition-related increases. These repetition effects were differentially sensitive to recognition with only activation in hippocampus and parahippocampal cortex tracking recognized items. These imaging findings converge with studies of amnesia and indicate dissociable roles for hippocampus in learning that supports explicit recognition and for anterior MTL cortex in configural learning.

Medial temporal lobe atrophy scores translated to clinical practice: Editorial comment on ‘Influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut‐offs'

Efferent connections of the anteromedial nucleus of the thalamus of the rat

The present study compared four different structural magnetic resonance imaging (MRI) techniques used to measure gray matter atrophy in Alzheimer's disease (AD): manual and automated volumetry, cortical thickness (CT) and voxel-based morphometry (VBM)). These techniques are used interchangeably in AD research and thus far it is unclear which technique is superior in detecting abnormalities early in the disease process. We inquired whether these techniques show similar results in healthy controls (con), patients with amnestic mild cognitive impairment (MCI) and patients suffering from mild AD. In addition, we investigated whether atrophy of prefrontal cortex (PFC) or medial temporal lobe (MTL) regions is most indicative of (preclinical) AD. Three groups of older male participants were selected: 18 healthy participants without any memory impairment, 18 patients with amnestic MCI, and 18 patients with mild AD. Between-group differences were investigated in PFC and MTL regions. A manual and automatic tracing approach were applied to calculate gray matter volume. CT was furthermore calculated by Freesurfer as the average thickness of the cortical surface in each ROI. VBM was applied by using masks of atlas-based ROI's in FSL. Manually measured right parahippocampal gyrus (PHG) volumes can differentiate con and MCI. Con and AD can furthermore be distinguished by manually measured hippocampus and PHG volumes, and by automated measurements of hippocampus and entorhinal cortex (ERC). Manual segmentation techniques are also sensitive for changes in PFC areas showing abnormalities in inferior and orbital PFC (con /AD and MCI/AD). CT analysis showed differences between con and AD in ERC, right inferior prefrontal (IPFC) and left medial orbitofrontal cortex (OFC) regions. VBM-ROI analyses showed differences between con/AD and MCI/AD in hippocampus, IPFC and OPFC (Table 1). The present study demonstrates that manual volumetry and VBM are able to detect group differences in both PFC and MTL structures (con/AD and MCI/AD). Manual volumetry of the right PhG can furthermore differentiate between con and MCI. The present study confirms earlier theories that the MTL is most indicative of (preclinical) AD, showing abnormalities in all the investigated techniques.

The present report deals with the projections from the entorhinal and perirhinal cortices to subcortical forebrain structures and the brainstem in the cat. By using anterograde and retrograde tracing techniques, it could be demonstrated that the entire mediolateral extent of the parahippocampal cortex issues prominent projections to the dorsal and ventral striatum, the amygdala, and the claustrum. In addition, the entorhinal cortex sends projections to the septum and the diagonal band of Broca. Only the perirhinal cortex gives rise to a weak projection to the dorsolateral periaquaductal gray and the ventral pontine region. The major proportion of the subcortical projections originates in the perirhinal cortex and the lateral entorhinal cortex, whereas the medial entorhinal cortex has a much sparser output and sends no fibers to the amygdala. The subcortical projections from both the entorhinal cortex and the perirhinal cortex arise mostly from their deep layers. It was further found that these projections are topographically organized along the mediolateral axis of the parahippocampal cortex. This mediolateral axis is related to a ventrolateral to dorsomedial axis in the septum, a mediolateral axis in the amygdala and the ventral striatum, and a ventrodorsal coordinate in the dorsal striatum and the claustrum. A further topography was observed in the projections from the perirhinal cortex to the lateral amygdaloid nucleus. A rostrocaudal axis in the perirhinal cortex corresponds to a mediolateral axis in the lateral amygdaloid nucleus. The present observations are compared with data concerning the connectivity of the parahippocampal cortex with the hippocampal formation and other cortical structures. It is suggested that the parahippocampal cortex in the cat may be conceptualized as an interface between the hippocampal formation and several subcortical structures in the realm of the limbic and motor systems.