Anterior Medial Temporal Lobe Research Articles

Insights from simultaneous EEG-fMRI and patient data illuminate the role of the anterior medial temporal lobe in N400 generation

The N400, a negative event-related potential (ERP) peaking approximately 400 ms after stimulus onset, is known to reflect the processing of semantic information. While scalp recordings have contributed to understanding the psychological processes underlying the N400, they have been limited in identifying its neural basis. However, recent intracranial ERP recordings and fMRI studies have shed light on the crucial role of the anterior medial temporal lobe (AMTL) in semantic information processing. These findings suggest that the N400 partially represents activity in the AMTL structures. To investigate the neural underpinnings of the N400 effect, we simultaneously recorded ERPs and event-related fMRI during a semantic priming paradigm in a sample of 12 young, healthy subjects. Additionally, we collected ERPs and structural brain data from older healthy adults and patients with amnestic mild cognitive impairment (aMCI), a population characterized by neurodegenerative changes in the AMTL. In our fMRI results, we identified bilateral loci in the AMTL as the global maxima. Employing an EEG-informed fMRI analysis, we explored trial-to-trial fluctuations in semantic processing by linking single-trial N400 amplitudes to the Blood Oxygen Level Dependent (BOLD) signal. This approach provided the first direct evidence linking the N400 recorded at the scalp level to the corresponding BOLD signal in the AMTL. Consistent with these findings, patients with aMCI exhibited a diminished N400 effect compared to healthy older adults. Furthermore, voxel-based morphometry analysis revealed a correlation between the magnitude of the N400 effect and the integrity of the AMTL. By integrating data from simultaneous EEG-fMRI, and patient studies, our research advances our understanding of the neural substrate of the N400 and highlights the critical involvement of the AMTL in semantic processing.

Medial temporal lobe gray matter microstructure alterations provide improved sensitivity to detect neurodegeneration associated with Alzheimer’s disease biomarkers

AbstractBackgroundDespite the strengths conventional structural imaging measures to detect atrophy, cross‐sectional relationships between neurodegeneration and Alzheimer’s disease (AD) biomarkers in early stages is limited. Neurite orientation dispersion and density imaging (NODDI) measures microstructural alterations that are unique from conventional structural metrics. Alterations in microstructure have been detected in individuals with AD compared to cognitively normal individuals, but there is sparse data regarding the relationship between these metrics and AD biomarkers. Here we sought to characterize how NODDI metrics in the medial temporal lobe (MTL) are associated with plasma AD biomarkers.MethodOne‐hundred and sixty‐seven cognitively normal (CN) individuals, 47 individuals with mild cognitive impairment, and 16 individuals with AD underwent diffusion and T1w imaging. T1w images were segmented using the ASHS‐T1 protocol to form anterior and posterior MTL ROIs. Multi‐shell DTI data were collected in 113 non‐collinear directions with 1.5mm isotropic voxels, were pre‐processed using a custom pipeline, and fit with voxel‐wise NODDI models. ANTs was used to linearly register NODDI and T1w images to allow transformation of MTL ROIs to diffusion space. Stepwise‐regression models examined relationships between anterior and posterior MTL NODDI metrics with plasma biomarkers in CN and impaired (MCI/AD) groups after accounting for MTL volume.ResultNODDI metrics of intracellular volume fraction (icVf) and orientation dispersion index (ODI) were decreased, and isometric volume fraction (isoVf) was increased in cognitively impaired compared to CN. Amyloid positivity was associated with decreased ODI and increased isoVf in cognitively impaired individuals. While posterior MTL volume predicted plasma p‐Tau‐181, inclusion of NODDI metrics subsumed this effect (F‐change>7.54, p<0.0067), and reduced ODI was the best predictor of plasma pTau‐181 within cognitively impaired individuals, while isoVf best predicted pTau‐181 across all individuals. Posterior MTL volume did not predict plasma GFAP, but inclusion of ODI and icVf both significantly predicted plasma GFAP in both CN and impaired individuals (F‐change>12.68, p<.001). Anterior MTL icVf predicted both pTau‐181 and GFAP.ConclusionMicrostructural alterations measured by NODDI appear more closely linked to AD‐related molecular measures and, thus, may provide a more sensitive cross‐sectional measure of neurodegeneration of the MTL compared to conventional macrostructural metrics.

Medial temporal lobe gray matter microstructure alterations provide improved sensitivity to detect neurodegeneration associated with Alzheimer’s disease biomarkers

AbstractBackgroundDespite the strengths conventional structural imaging measures to detect atrophy, cross‐sectional relationships between neurodegeneration and Alzheimer’s disease (AD) biomarkers in early stages is limited. Neurite orientation dispersion and density imaging (NODDI) measures microstructural alterations that are unique from conventional structural metrics. Alterations in microstructure have been detected in individuals with AD compared to cognitively normal individuals, but there is sparse data regarding the relationship between these metrics and AD biomarkers. Here we sought to characterize how NODDI metrics in the medial temporal lobe (MTL) are associated with plasma AD biomarkers.MethodOne‐hundred and sixty‐seven cognitively normal (CN) individuals, 47 individuals with mild cognitive impairment, and 16 individuals with AD underwent diffusion and T1w imaging. T1w images were segmented using the ASHS‐T1 protocol to form anterior and posterior MTL ROIs. Multi‐shell DTI data were collected in 113 non‐collinear directions with 1.5mm isotropic voxels, were pre‐processed using a custom pipeline, and fit with voxel‐wise NODDI models. ANTs was used to linearly register NODDI and T1w images to allow transformation of MTL ROIs to diffusion space. Stepwise‐regression models examined relationships between anterior and posterior MTL NODDI metrics with plasma biomarkers in CN and impaired (MCI/AD) groups after accounting for MTL volume.ResultNODDI metrics of intracellular volume fraction (icVf) and orientation dispersion index (ODI) were decreased, and isometric volume fraction (isoVf) was increased in cognitively impaired compared to CN. Amyloid positivity was associated with decreased ODI and increased isoVf in cognitively impaired individuals. While posterior MTL volume predicted plasma p‐Tau‐181, inclusion of NODDI metrics subsumed this effect (F‐change>7.54, p<0.0067), and reduced ODI was the best predictor of plasma pTau‐181 within cognitively impaired individuals, while isoVf best predicted pTau‐181 across all individuals. Posterior MTL volume did not predict plasma GFAP, but inclusion of ODI and icVf both significantly predicted plasma GFAP in both CN and impaired individuals (F‐change>12.68, p<.001). Anterior MTL icVf predicted both pTau‐181 and GFAP.ConclusionMicrostructural alterations measured by NODDI appear more closely linked to AD‐related molecular measures and, thus, may provide a more sensitive cross‐sectional measure of neurodegeneration of the MTL compared to conventional macrostructural metrics.

Aging and Alzheimer’s Disease Have Dissociable Effects on Local and Regional Medial Temporal Lobe Connectivity

AbstractBackgroundThe extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional disruption of the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity (FC) alterations between anterior and posterior regions of the MTL and in MTL‐associated functional communities – the Anterior‐Temporal (AT) and Posterior‐Medial (PM) networks – in normal agers, individuals with preclinical AD, and patients with Mild Cognitive Impairment or mild dementia due to AD.MethodIn this cross‐sectional study, we analyzed data from 179 individuals from the Aging Brain Cohort study of the Penn ADRC. Detailed information about participants is provided in Table 1. For intra‐MTL FC comparisons, the MTL subregions were segmented using the automated segmentation of hippocampal subfields‐T1 (ASHS‐T1) pipeline (Fig. 1a). When modeling the MTL’s interactions with the rest of the cortex, we employed four MTL ROIs (left/right × anterior/posterior) derived from an ex vivo atlas of tau accumulation in the MTL. Our functional datasets were preprocessed using a customized fMRIprep pipeline. Sparse network estimations and modularity‐based consensus clustering were used to reconstruct the AT and PM network systems (Fig. 1b). Age effect analyses and group comparisons along the AD continuum were performed using the General Linear Model within the network‐based statistical framework.ResultsThe preclinical stage of AD was characterized by increased FC between the perirhinal cortex and other regions of the MTL, as well as between the anterior MTL and its direct neighbors in the AT network (Fig. 1c‐d). This effect was not present in symptomatic AD. Instead, symptomatic patients displayed reduced hippocampal and intra‐PM connectivity. For normal aging, our results led to three main conclusions (for visuals, see Fig. 2). First, intra‐network connectivity of both the AT and PM networks decreases with age. Second, FC between the anterior and posterior segments of the MTL declines with age. Finally, within the MTL, we observed greater vulnerability of the posterior MTL subregions, particularly the parahippocampal cortex, to age‐associated FC decline.ConclusionTogether, the current results provide evidence for aberrant connectivity in the preclinical stage of AD that may have implications for early AD pathophysiology.

Aging and Alzheimer’s Disease Have Dissociable Effects on Local and Regional Medial Temporal Lobe Connectivity

AbstractBackgroundThe extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional disruption of the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity (FC) alterations between anterior and posterior regions of the MTL and in MTL‐associated functional communities – the Anterior‐Temporal (AT) and Posterior‐Medial (PM) networks – in normal agers, individuals with preclinical AD, and patients with Mild Cognitive Impairment or mild dementia due to AD.MethodIn this cross‐sectional study, we analyzed data from 179 individuals from the Aging Brain Cohort study of the Penn ADRC. Detailed information about participants is provided in Table 1. For intra‐MTL FC comparisons, the MTL subregions were segmented using the automated segmentation of hippocampal subfields‐T1 (ASHS‐T1) pipeline (Fig. 1a). When modeling the MTL’s interactions with the rest of the cortex, we employed four MTL ROIs (left/right × anterior/posterior) derived from an ex vivo atlas of tau accumulation in the MTL. Our functional datasets were preprocessed using a customized fMRIprep pipeline. Sparse network estimations and modularity‐based consensus clustering were used to reconstruct the AT and PM network systems (Fig. 1b). Age effect analyses and group comparisons along the AD continuum were performed using the General Linear Model within the network‐based statistical framework.ResultThe preclinical stage of AD was characterized by increased FC between the perirhinal cortex and other regions of the MTL, as well as between the anterior MTL and its direct neighbors in the AT network (Fig. 1c‐d). This effect was not present in symptomatic AD. Instead, symptomatic patients displayed reduced hippocampal and intra‐PM connectivity. For normal aging, our results led to three main conclusions (for visuals, see Fig. 2). First, intra‐network connectivity of both the AT and PM networks decreases with age. Second, FC between the anterior and posterior segments of the MTL declines with age. Finally, within the MTL, we observed greater vulnerability of the posterior MTL subregions, particularly the parahippocampal cortex, to age‐associated FC decline.ConclusionTogether, the current results provide evidence for aberrant connectivity in the preclinical stage of AD that may have implications for early AD pathophysiology.

Mapping Medial Temporal Lobe Longitudinal Change in Preclinical Alzheimer’s Disease

AbstractBackgroundThe medial temporal lobe (MTL) is a site of early tau pathology and neurodegeneration in AD. In recent work [1], we reported that rates of change in MTL subregion volumes on longitudinal structural T1‐MRI differ significantly between cognitively unimpaired individuals with and without amyloid pathology (A+CU vs A‐CU), suggesting that these measures are effective biomarkers for tracking disease progression in preclinical AD. Here, we develop a specialized pipeline that quantifies pointwise longitudinal change across the MTL, revealing more informative spatial patterns of early neurodegeneration than summary volumetric longitudinal measures.MethodOur pipeline, SkelDBM, combines skeletonization and deformation‐based morphometry to generate maps of annualized rate of atrophy on the skeleton of an MTL template (Figure 1). SkelDBM samples subjects’ atrophy maps along the skeleton of an MTL template, increasing robustness to subject‐to‐template registration errors. We evaluate SkelDBM using a subset of ADNI data studied in [1] (Table 1). Two preclinical AD groups (A+CU and tau‐positive A+CU) are compared to a control group (A‐CU) using general linear models (GLM) with age as nuisance covariate; permutation testing is used to derive statistically significant clusters.ResultThe full A+CU vs A‐CU comparison shows significant differences in rates of change in right anterior hippocampus, right entorhinal cortex, right transentorhinal cortex, and left posterior hippocampus (Figure 2). Limiting the A+CU group to tau‐positive individuals yields more widespread differences, including most of the right anterior MTL cortex and both hippocampi. These patterns align with volumetric longitudinal data reported in [1] but provide a richer characterization of spatial atrophy patterns.ConclusionSkelDBM is sensitive to longitudinal atrophy occurring over relatively short periods (∼2 years) in preclinical AD and characterizes patterns of atrophy more comprehensively than summary volumetric measures. Summary measures are also subject to biases, since larger structures are typically associated with less measurement error and hence may show exaggerated statistical effects compared to smaller structures even when the underlying neurodegeneration rates are the same. Regional maps of longitudinal change may be more robust to this bias and may help discovery of “signature regions” associated with specific pathological drivers of neurodegeneration. [1] Xie et al., Human Brain Mapping, 2020.

Developing an anatomically valid segmentation protocol for early tau regions: the anterior medial temporal lobe cortices

AbstractBackgroundThe anterior portion of the medial temporal lobe (MTL) is one of the earliest regions showing tau deposition in Alzheimer’s disease (AD) and hence a key focus area for AD imaging biomarkers. However, the anatomical variability of the anterior MTL presents a challenge for segmentation protocols. Leveraging a novel postmortem dataset with histology and MRI, we aimed to develop a histologically‐informed segmentation protocol for the anterior entorhinal cortex (ERC), Brodmann Area (BA) 35 (approximates transentorhinal cortex), and BA36 for in vivo 3 tesla (T) MRI.MethodDigitized 50‐µm thick MTL Nissl‐stained coronal histology sections from 20 cases (Table 1) were annotated by expert neuroanatomists. Cases with and without neurodegenerative diseases were included to ensure broad generalizability of the protocol. The histology sections were registered to same‐subject 0.2×0.2×0.2‐mm3 9.4 T postmortem MRI and were analyzed together to determine the location of the histological borders of the MTL cortices in relation to anatomical landmarks observable on MRI.ResultThe distance between the anterior histological border of ERC, BA35 and BA36 was assessed in relation to different anatomical landmarks observable on MRI. The distance relative to the hippocampus was chosen, as there was relatively low between‐subject variability in distance (low SD in Table 2) and this region is easily identifiable on MRI. The ERC starts 4.75 mm (median) anterior to the hippocampus, BA35 9.25 mm and BA36 10.25 mm. There was no significant difference in distances between patients with and without neurodegenerative disease. Next, we analyzed the location of the ERC on histology sections. We determined that regardless of the depth of the collateral sulcus (CS) (contrary to more posterior regions), the inferior border of the ERC is on average at the edge of the CS and the superior border at the superior edge of the parahippocampal gyrus (Figure 1a), but at the halfway point for the first section with ERC. These segmentation rules for ERC can be applied to T1‐MRI (Figure 1b).ConclusionSegmentation rules for anterior BA35 and BA36 are under development. This histologically‐informed segmentation protocol is expected to improve the efficacy of imaging biomarkers for tau deposition in AD.

Mapping Medial Temporal Lobe Longitudinal Change in Preclinical Alzheimer’s Disease

AbstractBackgroundThe medial temporal lobe (MTL) is a site of early tau pathology and neurodegeneration in AD. In recent work [1], we reported that rates of change in MTL subregion volumes on longitudinal structural T1‐MRI differ significantly between cognitively unimpaired individuals with and without amyloid pathology (A+CU vs A‐CU), suggesting that these measures are effective biomarkers for tracking disease progression in preclinical AD. Here, we develop a specialized pipeline that quantifies pointwise longitudinal change across the MTL, revealing more informative spatial patterns of early neurodegeneration than summary volumetric longitudinal measures.MethodsOur pipeline, SkelDBM, combines skeletonization and deformation‐based morphometry to generate maps of annualized rate of atrophy on the skeleton of an MTL template (Figure 1). SkelDBM samples subjects’ atrophy maps along the skeleton of an MTL template, increasing robustness to subject‐to‐template registration errors. We evaluate SkelDBM using a subset of ADNI data studied in [1] (Table 1). Two preclinical AD groups (A+CU and tau‐positive A+CU) are compared to a control group (A‐CU) using general linear models (GLM) with age as nuisance covariate; permutation testing is used to derive statistically significant clusters.ResultsThe full A+CU vs A‐CU comparison shows significant differences in rates of change in right anterior hippocampus, right entorhinal cortex, right transentorhinal cortex, and left posterior hippocampus (Figure 2). Limiting the A+CU group to tau‐positive individuals yields more widespread differences, including most of the right anterior MTL cortex and both hippocampi. These patterns align with volumetric longitudinal data reported in [1] but provide a richer characterization of spatial atrophy patterns.ConclusionSkelDBM is sensitive to longitudinal atrophy occurring over relatively short periods (∼2 years) in preclinical AD and characterizes patterns of atrophy more comprehensively than summary volumetric measures. Summary measures are also subject to biases, since larger structures are typically associated with less measurement error and hence may show exaggerated statistical effects compared to smaller structures even when the underlying neurodegeneration rates are the same. Regional maps of longitudinal change may be more robust to this bias and may help discovery of “signature regions” associated with specific pathological drivers of neurodegeneration.[1] Xie et al., Human Brain Mapping, 2020.

Verbal fluency discrepancies as a marker of the prehippocampal stages of Alzheimer's disease.

Prior to evidence of episodic memory decline, a lengthy preclinical phase of Alzheimer's disease (AD) exists characterized by the build-up of tau pathology within extrahippocampal structures. Semantic memory, also impaired in AD, has been linked to degradation within these earliest affected areas. This study aimed to assess the utility of performance discrepancies between letter and category verbal fluency tasks to detect neuronal loss in brain regions affected very early by AD. Whole-brain voxel-based morphometry was used to assess the neural correlates of semantic processing in three patient groups: two groups of mild cognitive impairment (MCI) patients split into mildly (n = 58) and moderately (n = 53) affected and a mild AD dementia group (n = 71). Discrepancies between the level of impairment on the semantic category fluency test and nonsemantic letter fluency test were calculated for each participant and included in regression models measuring the relationship between semantic memory and whole-brain gray matter volume. Patients at all disease stages demonstrated a loss of the normal semantic advantage in fluency tests, showing significantly greater impairments in category relative to letter fluency. Discrepancy scores in mild MCI correlated strongly with the structural integrity of the anterior medial temporal lobes. Correlations in more severely affected groups were weaker and more widespread. Semantic memory appears a useful indicator of even the earliest stages of medial temporal damage in AD. With advancing disease severity, the discrepancy index loses its focal anatomical association, reinforcing its value as an early marker of incipient decline. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Aging and Alzheimer's disease have dissociable effects on local and regional medial temporal lobe connectivity.

Functional disruption of the medial temporal lobe-dependent networks is thought to underlie episodic memory deficits in aging and Alzheimer's disease. Previous studies revealed that the anterior medial temporal lobe is more vulnerable to pathological and neurodegenerative processes in Alzheimer's disease. In contrast, cognitive and structural imaging literature indicates posterior, as opposed to anterior, medial temporal lobe vulnerability in normal aging. However, the extent to which Alzheimer's and aging-related pathological processes relate to functional disruption of the medial temporal lobe-dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity alterations in the medial temporal lobe and its immediate functional neighbourhood-the Anterior-Temporal and Posterior-Medial brain networks-in normal agers, individuals with preclinical Alzheimer's disease and patients with Mild Cognitive Impairment or mild dementia due to Alzheimer's disease. In the Anterior-Temporal network and in the perirhinal cortex, in particular, we observed an inverted 'U-shaped' relationship between functional connectivity and Alzheimer's stage. According to our results, the preclinical phase of Alzheimer's disease is characterized by increased functional connectivity between the perirhinal cortex and other regions of the medial temporal lobe, as well as between the anterior medial temporal lobe and its one-hop neighbours in the Anterior-Temporal system. This effect is no longer present in symptomatic Alzheimer's disease. Instead, patients with symptomatic Alzheimer's disease displayed reduced hippocampal connectivity within the medial temporal lobe as well as hypoconnectivity within the Posterior-Medial system. For normal aging, our results led to three main conclusions: (i) intra-network connectivity of both the Anterior-Temporal and Posterior-Medial networks declines with age; (ii) the anterior and posterior segments of the medial temporal lobe become increasingly decoupled from each other with advancing age; and (iii) the posterior subregions of the medial temporal lobe, especially the parahippocampal cortex, are more vulnerable to age-associated loss of function than their anterior counterparts. Together, the current results highlight evolving medial temporal lobe dysfunction in Alzheimer's disease and indicate different neurobiological mechanisms of the medial temporal lobe network disruption in aging versus Alzheimer's disease.

Relationships between age, fMRI correlates of familiarity and familiarity-based memory performance under single and dual task conditions

Using fMRI, we investigated the effects of age and divided attention on the neural correlates of familiarity and their relationship with memory performance. At study, word pairs were visually presented to young and older participants under the requirement to make a relational judgment on each pair. Participants were then scanned while undertaking an associative recognition test under single and dual (auditory tone detection) task conditions. The test items comprised studied, rearranged (words from different studied pairs) and new word pairs. fMRI familiarity effects were operationalized as greater activity elicited by studied pairs incorrectly identified as ‘rearranged’ than by correctly rejected new pairs. The reverse contrast was employed to identify ‘novelty’ effects. Behavioral familiarity estimates were equivalent across age groups and task conditions. Robust fMRI familiarity effects were identified in several regions, including medial and superior lateral parietal cortex, dorsal medial and left lateral prefrontal cortex, and bilateral caudate. fMRI novelty effects were identified in the anterior medial temporal lobe. Both familiarity and novelty effects were largely age-invariant and did not vary, or varied minimally, according to task condition. In addition, the familiarity effects correlated positively with a behavioral estimate of familiarity strength irrespective of age. These findings extend a previous report from our laboratory, and converge with prior behavioral reports, in demonstrating that the factors of age and divided attention have little impact on behavioral and neural estimates of familiarity.

Dissociating distinct cortical networks associated with subregions of the human medial temporal lobe using precision neuroimaging

Tract-tracing studies in primates indicate that different subregions of the medial temporal lobe (MTL) are connected with multiple brain regions. However, no clear framework defining the distributed anatomy associated with the human MTL exists. This gap in knowledge originates in notoriously low MRI data quality in the anterior human MTL and in group-level blurring of idiosyncratic anatomy between adjacent brain regions, such as entorhinal and perirhinal cortices, and parahippocampal areas TH/TF. Using MRI, we intensively scanned four human individuals and collected whole-brain data with unprecedented MTL signal quality. Following detailed exploration of cortical networks associated with MTL subregions within each individual, we discovered three biologically meaningful networks associated with the entorhinal cortex, perirhinal cortex, and parahippocampal area TH, respectively. Our findings define the anatomical constraints within which human mnemonic functions must operate and are insightful for examining the evolutionary trajectory of the MTL connectivity across species.

Psychological stress is associated with arterial inflammation in people living with treated HIV infection

Stress and depression are increasingly recognized as cerebrovascular risk factors, including among high stress populations such as people living with HIV infection (PLWH). Stress may contribute to stroke risk through activation of neural inflammatory pathways. In this cross-sectional study, we examined the relationships between stress, systemic and arterial inflammation, and metabolic activity in stress-related brain regions on 18F-fluorodeoxyglucose (FDG)-PET in PLWH. Participants were recruited from a parent trial evaluating the impact of alirocumab on radiologic markers of cardiovascular risk in people with treated HIV infection. We administered a stress battery to assess different forms of psychological stress, specifying the Perceived Stress Scale as the primary stress measure, and quantified plasma markers of inflammation and immune activation. Participants underwent FDG-PET of the brain, neck, and chest. Age- and sex-matched control participants without HIV infection were selected for brain FDG-PET comparisons. Among PLWH, we used nonparametric pairwise correlations, partial correlations, and linear regression to investigate the association between stress and 1) systemic inflammation; 2) atherosclerotic inflammation on FDG-PET; and metabolic activity in 3) brain regions in which glucose metabolism differed significantly by HIV serostatus; and 4) in a priori defined stress-responsive regions of interest (ROI) and stress-related neural network activity (i.e., ratio of amygdala to ventromedial prefrontal cortex or temporal lobe activity). We studied 37 PLWH (mean age 60 years, 97% men) and 29 control participants without HIV (mean age 62 years, 97% men). Among PLWH, stress was significantly correlated with systemic inflammation (r = 0.33, p = 0.041) and arterial inflammation in the carotid (r = 0.41, p = 0.023) independent of age, race/ethnicity, traditional vascular risk factors and health-related behaviors. In voxel-wise analyses, metabolic activity in a cluster corresponding to the anterior medial temporal lobes, including the bilateral amygdalae, was significantly lower in PLWH compared with controls. However, we did not find a significant positive relationship between stress and this cluster of decreased metabolic activity in PLWH, a priori defined stress-responsive ROI, or stress-related neural network activity. In conclusion, psychological stress was associated with systemic and carotid arterial inflammation in this group of PLWH with treated infection. These data provide preliminary evidence for a link between psychological stress, inflammation, and atherosclerosis as potential drivers of excess cerebrovascular risk among PLWH.

Verbal memory formation across PET-based Braak stages of tau accumulation in Alzheimer's disease.

A classical early sign of typical Alzheimer's disease is memory decline, which has been linked to the aggregation of tau in the medial temporal lobe. Verbal delayed free recall and recognition tests have consistently probed useful to detect early memory decline, and there is substantial debate on how performance, particularly in recognition tests, is differentially affected through health and disease in older adults. Using in vivo PET-Braak staging, we investigated delayed recall and recognition memory dysfunction across the Alzheimer's disease spectrum. Our cross-sectional study included 144 cognitively unimpaired elderly, 39 amyloid-β+ individuals with mild cognitive impairment and 29 amyloid-β+ Alzheimer's disease patients from the Translational Biomarkers in Aging and Dementia cohort, who underwent [18F]MK6240 tau and [18F]AZD4694 amyloid PET imaging, structural MRI and memory assessments. We applied non-parametric comparisons, correlation analyses, regression models and voxel-wise analyses. In comparison with PET-Braak Stage 0, we found that reduced, but not clinically significant, delayed recall starts at PET-Braak Stage II (adjusted P < 0.0015), and that recognition (adjusted P = 0.011) displayed a significant decline starting at PET-Braak Stage IV. While performance in both delayed recall and recognition related to tau in nearly the same cortical areas, further analyses showed that delayed recall rendered stronger associations in areas of early tau accumulation, whereas recognition displayed stronger correlations in mostly posterior neocortical regions. Our results support the notion that delayed recall and recognition deficits are predominantly associated with tau load in allocortical and neocortical areas, respectively. Overall, delayed recall seems to be more dependent on the integrity of anterior medial temporal lobe structures, while recognition appears to be more affected by tau accumulation in cortices beyond medial temporal regions.

18F‐fluorodeoxyglucose‐positron emission tomography Findings in Patients with Genetic Frontotemporal Dementia

AbstractBackgroundMutations in microtubule‐associated protein tau (MAPT), granulin (GRN), and hexanucleotide expansion repeat in the open reading frame of chromosome 9 (C9orf72) are found in 60% of familial frontotemporal dementia (FTD) cases. The current study aims to delineate brain regions with reduced glucose metabolism in patients with genetic FTD in comparison with cognitively normal controls.Methods(18)F‐ fluorodeoxyglucose (FDG)‐positron emission tomography (PET) images were retrospectively obtained from 17 genetic FTD patients. All patients were symptomatic at the time of imaging, and the autopsy was available for 13. Pittsburgh compound B (PiB) amyloid PET scans were done for 13 patients (Table 1). FDG‐PET was collected at Lawrence Berkeley National Laboratory on a PET or PET‐CT scanner as six 5‐min frames acquired 30 min post tracer injection. Standard Uptake Value Ratio (SUVR) images were created for each patient using pons as a reference region. W‐score (age‐adjusted Z‐score) maps were created for each patient’s FDG SUVR using a group of neurologically unimpaired controls (N=74, Mean age 65+16, 41 female) as reference.ResultOn review of single‐subject w‐maps, all patients with MAPT mutation showed hypometabolism in the anteromedial temporal lobes with 66% showing anterolateral temporal hypometabolism and 33% in the frontal and dorsolateral parietal lobes. Hypometabolism in temporal lobes was seen in all GRN patients and 75% had frontal and parietal hypometabolism in an asymmetric pattern. 80% of theC9orf72 patients had hypometabolism in anteromedial temporal and orbitofrontal regions. 60% showed hypometabolism in dorsolateral prefrontal, medial frontal, and anterolateral temporal lobes. Posterior temporal, posterior cingulate, parietal lobe, cerebellum, insula, thalamus, and caudate were hypometabolic in less than 40% of the C9orf72 patients (Figure 1).On group‐level analysis, compared to controls, patients with C9orf72 showed hypometabolism in the frontotemporal regions, cerebellum and thalamus. Hypometabolism in the frontotemporal and parietal regions was seen with GRN mutation. MAPT mutation carriers showed frontal and anteromedial temporal hypometabolism (Figure 2).ConclusionHypometabolism in the posterior regions and cerebellum is more suggestive of C9orf72 repeat expansion. An asymmetric pattern of hypometabolism was seen in all GRN mutation carriers. MAPT mutation resulted in a greater degree of hypometabolism in the anterior medial temporal lobes.

Verbal recognition declines in later Braak Stages compared to verbal delayed recall

AbstractBackgroundEpisodic memory decline is a hallmark of cognitive impairment due to Alzheimer’s Disease (AD). Literature has consistently indicated that delayed recall is compromised early in the disease. Recognition memory seems disrupted at late stages, although findings are mixed. Recent PET studies have demonstrated that the presence of tau in the medial temporal lobe (MTL) relates to early deterioration of delayed recall, but no PET studies have assessed how recognition memory relates to tau. We sought to investigate this relationship across the Braak staging continuum.MethodTau PET ([18F]‐MK6240) was acquired for 140 cognitively unimpaired elderly (CU), 54 MCI patients and 33 AD patients. Participants were segregated into Braak stages, based on in vivo PET neuroimaging of tau. Episodic memory was assessed using RAVLT delayed recall and recognition tests. MRI were segmented into probabilistic grey (GM) and white (WM) maps, non‐linearly registered to the ADNI template using Dartel and smoothed with an 8mm FWHM gaussian kernel. Independent samples t‐tests or their nonparametric counterparts were conducted to evaluate differences in memory scores by Braak stage. Voxel‐wise linear regression models were applied, using VoxelStats, with either delayed recall or recognition scores as dependent variables and tau PET as a predictor. Global amyloid, age, sex, education and APOE genotype were entered as covariates.ResultsPairwise comparisons revealed that recognition memory is spared in early Braak stages. Voxel‐wise analyses in the whole sample unveiled that delayed recall and recognition memory relate to tau in virtually the same cortical areas. However, the strength of the relationships widely varied by memory type. Tau‐PET in anterior MTL and posterior hippocampus shows stronger associations with delayed recall, while tau binding in lateral temporal, temporooccipital and posterior areas exhibits stronger associations with recognition memory.ConclusionOur findings support the differentiation between delayed recall and recognition across the AD spectrum. Relationships between delayed recall and tau in the MTL are in concordance with previous research. Moreover, the contrast in the strength of the associations between memory and tau aggregation further supports the notion that delayed recall is already impaired in early Braak stages while recognition is damaged in later Braak stages.

Evidence for a single rather than a triple dissociation in the medial temporal lobe: An fMRI recognition memory replication study

Common research practices in neuroimaging studies using functional magnetic resonance imaging may produce outcomes that are difficult to replicate. Results that cannot be replicated have contributed to a replication crisis in psychology, neuroscience, and other disciplines over the years. Here we replicate two previous papers in which the authors present two analysis paths for a dataset in which participants underwent fMRI while performing a recognition memory test for old and new words. Both studies found activation in the medial temporal lobe including the hippocampus, with the first demonstrating a distinction in activation corresponding to true and perceived oldness of stimuli and the second demonstrating that activation reflects the subjective experience of the participant. We replicated the behavioral and MRI acquisition parameters reported in the two target articles (Daselaar et al., 2006; Daselaar et al., 2006) with N = 53 participants. We focused fMRI analyses on regions of interest reported in the target articles examining fMRI activation for differences corresponding with true and perceived oldness and those associated with the subjective memory experiences of recollection, familiarity, and novelty. Comparisons between true and perceived oldness revealed main effects not only for true, but also perceived oldness along with a significant interaction. We replicate the findings of recollection and familiarity signals in the hippocampus and medial temporal lobe cortex, respectively, but failed to replicate a novelty signal in the anterior medial temporal lobe. These results remained when we analyzed only correct trials, indicating that the effects were not due to selectively averaging correct and incorrect trials. Taken together, our findings demonstrate that activation in the hippocampus corresponds to the subjective experience associated with correct recognition memory retrieval.

Microglial Activation and Connectivity in Alzheimer Disease and Aging.

Alzheimer disease (AD) is characterized by amyloid β (Aβ) plaques and neurofibrillary tau tangles, but increasing evidence suggests that neuroinflammation also plays a key role, driven by the activation of microglia. Aβ and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive whether microglial activation follows a similar distribution pattern. Here, we assess whether connectivity is associated with microglia activation patterns. We included 32 Aβ-positive early AD subjects (18 women, 14 men) and 18 Aβ-negative age-matched healthy controls (10 women, 8 men) from the prospective ActiGliA (Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's Disease) study. All participants underwent microglial activation positron emission tomography (PET) with the third-generation mitochondrial 18 kDa translocator protein (TSPO) ligand [18 F]GE-180 and magnetic resonance imaging (MRI) to measure resting-state functional and structural connectivity. We found that inter-regional covariance in TSPO-PET and standardized uptake value ratio was preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker association with microglial activation. AD patients showed increased TSPO-PET tracer uptake bilaterally in the anterior medial temporal lobe compared to controls, and higher TSPO-PET uptake was associated with cognitive impairment and dementia severity in a disease stage-dependent manner. Microglial activation distributes preferentially along highly connected brain regions, similar to tau pathology. These findings support the important role of microglia in neurodegeneration, and we speculate that pathology spreads throughout the brain along vulnerable connectivity pathways. ANN NEUROL 2022;92:768-781.

P707. Hopelessness is Associated With Reduced Wide-Band Magnetoencephalographic Power in Anterior Medial Temporal Lobes in a Clinical Sample

Hopelessness, or pessimism about the future, is a predictor of suicidal thoughts and behaviors. Previous studies have implicated alterations in widespread brain regions, including the frontal cortex and medial temporal lobes (MTL), in suicidal ideation and attempt. However, limited research has examined relationships between suicide risk, hopelessness, and magnetoencephalography (MEG) power.

Volume of the posterior hippocampus mediates age-related differences in spatial context memory and is correlated with increased activity in lateral frontal, parietal and occipital regions in healthy aging

Healthy aging is associated with episodic memory decline, particularly in the ability to encode and retrieve object-context associations (context memory). Neuropsychological and neuroimaging studies have highlighted the importance of the medial temporal lobes (MTL) in supporting episodic memory across the lifespan. However, given the functional heterogeneity of the MTL, volumetric declines in distinct regions may impact performance on specific episodic memory tasks, and affect the function of the large-scale neurocognitive networks supporting episodic memory encoding and retrieval. In the current study, we investigated how MTL structure may mediate age-related differences in performance on spatial and temporal context memory tasks, in a sample of 125 healthy adults aged 19–76 years old. Standard T1-weighted MRIs were segmented into the perirhinal, entorhinal and parahippocampal cortices, as well as the anterior and posterior hippocampal subregions. We observed negative linear and quadratic associations between age and volume of the parahippocampal cortex, and anterior and posterior hippocampal subregions. We also found that volume of the posterior hippocampus fully mediated the association between age and spatial, but not temporal context memory performance. Further, we employed a multivariate behavior partial-least-squares analysis to assess how age and regional MTL volumes correlated with brain activity during the encoding and retrieval of spatial context memories. We found that greater activity within lateral prefrontal, parietal, and occipital regions, as well as within the anterior MTL was related to older age and smaller volume of the posterior hippocampus. Our results highlight the heterogeneity of MTL contributions to episodic memory across the lifespan and provide support for the posterior-anterior shift in aging, and scaffolding theory of aging and cognition.