Medial temporal lobe Tau-Neurodegeneration mismatch from MRI and plasma biomarkers identifies vulnerable and resilient phenotypes with AD.

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.

Decision letter: Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer’s disease continuum

BackgroundThe extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional alterations in the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. Here, we examined the relationship between tau accumulation in the (trans)entorhinal cortex and functional connectivity (FC) in two MTL‐affiliated brain networks — the Anterior‐Temporal (AT) and Posterior‐Medial (PM) — in normal agers, individuals with preclinical AD, and patients with symptomatic AD.MethodIn this cross‐sectional study, we analyzed data from 125 individuals from the Penn ADRC (Table 1). All participants underwent structural and functional MRI on a Siemens 3 T Prisma system, as well as 18F‐Florbetaben and 18F‐Flortaucipir (FTP) PET imaging. We used the AT/PM network architecture from our previous work (Fig. 1; PMID37767219) and analyzed the effects of (trans)entorhinal tau accumulation on the AT/PM FC as a function of distance to the MTL (Fig. 1). Guided by our previous findings of an inverted U‐shaped FC pattern in the AT network over the course of the disease, we performed separate analyses of the AT FC in cognitively normal and symptomatic individuals.ResultsFC between the anterior MTL and its direct neighbors in the AT network was positively correlated with tau accumulation in the MTL (r = 0.201, p = 0.031; Fig. 2a). Associations with tau were not present in other MTL‐AT connections (Figs. 2b‐c) or in individuals with symptomatic AD. In contrast, the PM FC was broadly affected by tau pathology with both direct MTL‐PM and more distant connections showing a negative relationship to (trans)entorhinal tau (Fig. 2d‐e). Excluding amyloid‐negative controls, the relationship between MTL tau and AT/PM FC remained statistically significant in the PM [one‐hop connections: r = ‐0.323, p = 0.0479; distant connections: r = ‐0.324, p = 0.047] but not the AT network.ConclusionsTogether, the current results implicate functional abnormalities in the AT network during the preclinical stage, while those in the PM network are closely related to disease severity. This dissociation likely represents distinct pathophysiology in AD and has potential implications for FC‐based metrics as a surrogate measure for assessing functional response to disease‐modifying immunotherapies.

BackgroundThe extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional alterations in the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. Here, we examined the relationship between tau accumulation in the (trans)entorhinal cortex and functional connectivity (FC) in two MTL‐affiliated brain networks — the Anterior‐Temporal (AT) and Posterior‐Medial (PM) — in normal agers, individuals with preclinical AD, and patients with symptomatic AD.MethodIn this cross‐sectional study, we analyzed data from 125 individuals from the Penn ADRC (Table 1). All participants underwent structural and functional MRI on a Siemens 3 T Prisma system, as well as 18F‐Florbetaben and 18F‐Flortaucipir (FTP) PET imaging. We used the AT/PM network architecture from our previous work (Figure 1; PMID37767219) and analyzed the effects of (trans)entorhinal tau accumulation on the AT/PM FC as a function of distance to the MTL (Figure 1). Guided by our previous findings of an inverted U‐shaped FC pattern in the AT network over the course of the disease, we performed separate analyses of the AT FC in cognitively normal and symptomatic individuals.ResultsFC between the anterior MTL and its direct neighbors in the AT network was positively correlated with tau accumulation in the MTL (r = 0.201, p = 0.031; Figure 2a). Associations with tau were not present in other MTL‐AT connections (Figures 2b‐c) or in individuals with symptomatic AD. In contrast, the PM FC was broadly affected by tau pathology with both direct MTL‐PM and more distant connections showing a negative relationship to (trans)entorhinal tau (Figure 2d‐e). Excluding amyloid‐negative controls, the relationship between MTL tau and AT/PM FC remained statistically significant in the PM [one‐hop connections: r = ‐0.323, p = 0.0479; distant connections: r = ‐0.324, p = 0.047] but not the AT network.ConclusionsTogether, the current results implicate functional abnormalities in the AT network during the preclinical stage, while those in the PM network are closely related to disease severity. This dissociation likely represents distinct pathophysiology in AD and has potential implications for FC‐based metrics as a surrogate measure for assessing functional response to disease‐modifying immunotherapies.

Intrinsic Connectivity Identifies the Hippocampus as a Main Crossroad between Alzheimer’s and Semantic Dementia-Targeted Networks

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

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

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

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

Mild cognitive impairment (MCI), particularly the amnestic subtype (aMCI), is considered as a transitional stage between normal aging and a diagnosis of clinically probable Alzheimer's disease (AD). The aMCI construct is particularly useful as it provides an opportunity to assess a clinical stage which in most subjects represents prodromal AD. The aim of this study was to assess the progression of cerebral atrophy over multiple serial MRI during the period from aMCI to progression to AD. Thirty-three subjects were selected that fulfilled clinical criteria for aMCI and had three serial MRI scans: the first scan approximately 3 years before the diagnosis of AD, the second scan approximately 1 year before, and the third scan at the time of the diagnosis of AD. A group of 33 healthy controls were age and gender-matched to the study cohort. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the aMCI subjects at each time-point compared to the control group. Customized templates and prior probability maps were used to avoid normalization and segmentation bias. The pattern of grey matter loss in the aMCI subject scans that were 3 years before the diagnosis of AD was focused primarily on the medial temporal lobes, including the amygdala, anterior hippocampus and entorhinal cortex, with some additional involvement of the fusiform gyrus, compared to controls. The extent and magnitude of the cerebral atrophy further progressed by the time the subjects were 1 year before the diagnosis of AD. At this point atrophy in the temporal lobes spread to include the middle temporal gyrus, and extended into more posterior regions of the temporal lobe to include the entire extent of the hippocampus. The parietal lobe also started to become involved. By the time the subjects had progressed to a clinical diagnosis of AD the pattern of grey matter atrophy had become still more widespread with more severe involvement of the medial temporal lobes and the temporoparietal association cortices and, for the first time, substantial involvement of the frontal lobes. This pattern of progression fits well with the Braak and Braak neurofibrillary pathological staging scheme in AD. It suggests that the earliest changes occur in the anterior medial temporal lobe and fusiform gyrus, and that these changes occur at least 3 years before progression to the diagnosis of AD. These results also suggest that 3D patterns of grey matter atrophy may help to predict the time to the first diagnosis of AD in subjects with aMCI.

IC-P-017: Different patterns of gray and white matter atrophy in Alzheimer’s disease and subtypes of frontotemproal lobar dementia

Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimer's disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimer's disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimer's disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left-sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimer's disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimer's disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role.

Tau deposition begins in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD), and MTL neural dysfunction is commonly observed in these groups. However, the association between tau and MTL neural activity has not been fully characterized. We investigated the effects of tau on repetition suppression, the reduction of activity for repeated stimulus presentations compared to novel stimuli. We used task-based functional MRI (fMRI) to assess MTL subregional activity in 21 young adults (YA) and 45 cognitively normal human older adults (OA; total sample: 37 females, 29 males). AD pathology was measured with position emission tomography (PET), using 18F-Flortaucipir for tau and 11C-Pittsburgh compound B (PiB) for amyloid-β (Aβ). The MTL was segmented into six subregions using high-resolution structural images. We compared the effects of low tau pathology, restricted to entorhinal cortex and hippocampus (Tau- OA), to high tau pathology, also occurring in temporal and limbic regions (Tau+ OA). Low levels of tau (Tau- OA vs YA) were associated with reduced repetition suppression activity specifically in anterolateral entorhinal cortex (alEC) and hippocampus, the first regions to accumulate tau. High tau pathology (Tau+ vs Tau- OA) was associated with widespread reductions in repetition suppression across MTL. Further analyses indicated that reduced repetition suppression was driven by hyperactivity to repeated stimuli, rather than decreased activity to novel stimuli. Increased activation was associated with entorhinal tau, but not Aβ. These findings reveal a link between tau deposition and neural dysfunction in MTL, in which tau-related hyperactivity prevents deactivation to repeated stimuli, leading to reduced repetition suppression.SIGNIFICANCE STATEMENT Abnormal neural activity occurs in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD). Because tau pathology first deposits in the MTL in aging, this altered activity may be due to local tau pathology, and distinct MTL subregions may be differentially vulnerable. We demonstrate that in older adults (OAs) with low tau pathology, there are focal alterations in activity in MTL subregions that first develop tau pathology, while OAs with high tau pathology have aberrant activity throughout MTL. Tau was associated with hyperactivity to repeated stimulus presentations, leading to reduced repetition suppression, the discrimination between novel and repeated stimuli. Our data suggest that tau deposition is related to abnormal activity in MTL before the onset of cognitive decline.

Patterns of signal from tau positron emission tomography (tau-PET) confined to the medial temporal lobe (MTL) or extended into the neocortex may be relevant for Alzheimer's disease (AD) research if they are linked to differential biomarker levels and cognitive decline. Visual assessment of Tau-PET [F-18]florquinitau (FQT) exams from 728 initially non-demented older adults yielded four uptake groups: tau-negative (T-), MTL-only (T+MTL), neocortex-only (T+Neo), or both (T+MTL&Neo). Mixed effects models assessed group differences in retrospective cognitive and plasma pTau217 trajectories. T+MTL&Neo was the most common T+ group (n=97; 93% A+) and exhibited the sharpest worsening in cognitive and pTau217 trajectories before tau PET. The T+MTL&Neo category represents an intermediate to advanced stage of AD preceded by rising ptau217 and progressive cognitive decline. The pTau217 finding suggests that A+, T+ in MTL or neocortex could represent early AD stages, with a higher likelihood of progressing to more advanced stages. Visual assessments of Tau-PET FQT revealed four distinct uptake groups: tau-negative (T-), MTL-only (T+MTL), neocortex-only (T+Neo), or both (T+MTL&Neo). Amyloid positive participants in the T+MTL and T+MTL&Neo categories showed a retrospectively faster decline in their cognitive trajectories, and a sharper increase in pTau217 levels in plasma, compared to T-. The T+MTL&Neo group displayed sharper trajectories compared with the other Tau positive groups in both their cognitive scores and pTau217 plasma levels. Our results suggest that participants with Tau present in both MTL and neocortex represent an intermediate to advanced stage of AD, whereas participants with signals confined to either MTL or neocortex could represent earlier AD stages.

Tau deposition patterns within the medial temporal lobe follow the connectivity of the entorhinal cortex – a combined post‐mortem and 7T fMRI study