Medial Temporal Lobe Regions Research Articles

Impact of cortical and subcortical atrophy in the diagnosis and prognosis of bvFTD: A multicenter longitudinal study

AbstractBackgroundThe behavioral variant of frontotemporal dementia (bvFTD) presents with variable patterns of cortical and subcortical atrophy on Magnetic Resonance Imaging (MRI). We aimed to assess the clinical utility of two reproducible measurements of cerebral atrophy (Harper's visual atrophy scale [HVAS], and the Magnetic Resonance Parkinsonism Index [MRPI]) in a large multicenter sample of bvFTD with longitudinal follow‐up.MethodsWe included 466 participants from three centers: 241 bvFTD (according to the International bvFTD Criteria Consortium), and 225 healthy controls (HC). Clinical deterioration was assessed with Mini‐Mental State Examination (MMSE) and the Clinical Deterioration Scale Sum‐of‐boxes (CDR‐sb). bvFTD participants were considered to have an increased certainty of underlying Frontotemporal Lobar Degeneration (+FTLD) when: (i) FTLD was confirmed at autopsy (n=72); (ii) a secondary FTLD‐related phenotype was identified during follow‐up (n=47) or (iii) a FTLD‐related mutation was found (n=49). Six raters blinded to clinical data were first asked to dichotomize participants according to the presence of "a clear pattern of atrophy suggestive of probable bvFTD", and then applied the HVAS (ICC(2,k)=.86 to .96). The MRPI was calculated with a fully automated algorithm.ResultsMean age of bvFTD participants was 63.3 ± 10, 68% were male (MMSE=23 ± 7 and CDR‐sb=6.7 ± 3.5). Blinded raters had 52% sensitivity and 97% specificity for the identification of bvFTD participants (AUC=.74, p=.001). All HVAS measures with the exception of posterior atrophy discriminated between bvFTD and HC (AUC=.77 to .83, p<.001). The composite bvFTD score (average score of orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe and frontal insula regions) showed the best diagnostic accuracy for the differentiation of bvFTD from HC (AUC=.91, p<.001 in +FTLD). This composite score also differentiated between bvFTD participants that were not considered to have a clear pattern of atrophy suggestive of probable bvFTD (blinded raters) and HC (p<.001). We hypothesized that HVAS and MRPI scores may be independent predictors of clinical deterioration and survival in bvFTD (definitive results pending).ConclusionThe combination of HVAS and MRPI may provide valuable diagnostic and prognostic information in the behavioral syndromes verifying bvFTD criteria. These measures represent reliable, reproducible and affordable imaging biomarkers.

Changes in anterior temporal and posterior medial hippocampal network connectivity in Alzheimer’s disease

AbstractBackgroundHippocampal connectivity is affected early in Alzheimer’s disease and plays a crucial role in episodic memory dysfunction. Different hippocampal subnetworks have been identified, namely the anterior temporal (AT) and the posterior medial (PM) networks that are specifically related to separate subregions of the medial temporal lobe (MTL) thought to be differentially affected in AD. The aim of this study was to assess the specific connectivity of these two networks and its changes in Alzheimer’s disease, using both a cross‐sectional and a longitudinal approach.MethodFifty‐three cognitively impaired patients on the Alzheimer’s continuum with mild cognitive impairment or dementia, all amyloid‐β (Aβ)‐positive, and 68 Aβ‐negative cognitively unimpaired elderly controls were included. They underwent structural T1‐MRI and resting‐state functional MRI (fMRI) scans at baseline and at 18‐month follow‐up as well for 30 patients. Seed‐based analyses were performed, using individual automatic segmentation of MTL subregions as seeds, to assess the functional connectivity within the AT (from the perirhinal cortex and anterior hippocampus seeds) and the PM (from the parahippocampal cortex and posterior hippocampus seeds) networks. First, we compared the functional connectivity of the two networks within the controls to highlight their specificities. Second, we compared MTL subregion connectivity within each network between groups, and between baseline and follow‐up in the patients, to assess AD‐related changes compared to controls and over time.ResultAT and PM networks showed distinct connectivity patterns in controls (Fig. 1). Patients showed decreased connectivity between the anterior hippocampus and regions of the PM network, and increased connectivity between anterior MTL subregions, compared to controls (Fig. 2). Over the 18‐month follow‐up period, decreased connectivity was found between both the anterior and posterior hippocampus and regions of the PM network, while increased connectivity was observed between several anterior MTL subregions and regions of the AT network (Fig. 3).ConclusionAD is characterized by both decreased MTL connectivity with the PM hippocampal network and increased connectivity with the AT hippocampal network. The specific assessment of the two main hippocampal subnetworks shed light on the overall pattern of AD‐related hippocampal changes involving both connectivity default and possible compensation or erroneous hyperactivity patterns.

High‐resolution postmortem MRI reveals TDP‐43 association with medial temporal lobe subregional atrophy

AbstractBackgroundThe medial temporal lobe (MTL) is a hotspot of different neurodegenerative pathologies, and recent studies have shown associations of severity of pathology with atrophy measured on antemortem MRI. However, these studies are limited by the interval between time of scan and death and the relatively low resolution of the commonly acquired in vivo MRI scans, limiting the granularity of the regions being measured. We investigate the association of different neurodegenerative pathologies, particularly TDP‐43, and the thickness of different MTL subregions measured on high‐resolution postmortem MRI. As prior work suggests an anterior‐to‐posterior gradient of atrophy for TDP‐43 in frontotemporal dementia spectrum disorders and Limbic‐predominant Age‐related TDP‐43 Encephalopathy (LATE), we also examined differences along the long axis of the MTL.MethodTau, TDP‐43, β‐amyloid and α‐synuclein pathology were rated (0‐absent – 3‐frequent) in the hippocampus and entorhinal cortex (ERC) of 35 individuals with and without neurodegenerative diseases (Table 1). Thickness measurements were obtained from 0.2x0.2x0.2 mm3 post‐mortem MRI scans of excised MTL specimens from the contralateral hemisphere (Figure 1) in the ERC, Brodmann Area 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare. For each region, thickness was measured at an anterior and posterior location using a semi‐automated approach (Figure 2). Spearman’s rank correlations were performed, correcting for age, sex and hemisphere, including all four proteinopathies in the model.ResultWe find strong negative associations of TDP‐43 with thickness in all cortical MTL regions (Table 2, Figure 3) and with CA1, averaged over the two locations. We repeated the analyses for the thickness measurements separately in the anterior and posterior locations, but did not find a clear difference along the longitudinal axis. This is potentially due to the severity of the TDP‐43 pathology.ConclusionIn this unique dataset with neurodegenerative pathologies and high‐resolution scans of the MTL, preliminary results show strong associations between TDP‐43 pathology and atrophy in several MTL subregions. As this dataset continues to grow, we will be able to tease apart the effects of multiple MTL pathologies at a subregional level.

Memory Impairments and Psychosis Prediction: A Scoping Review and Theoretical Overview.

Impairments in memory functions are among the most robust correlates of schizophrenia and of poor functional outcomes in individuals with psychotic disorders. Prospective, longitudinal studies are crucial to determining the meaning of these deficits in relation to mechanisms associated with the onset and course of these disorders.The objective of this review is to examine the literature concerning premorbid memory impairments during the prodromal phase of psychosis to address three primary questions 1) are memory impairments present among individuals with a clinical high risk syndrome? 2) are memory deficits in clinical high risk cases predictive of future conversion to psychosis? and 3) what are the underlying neural correlates of memory impairment in clinical high risk individuals and are they also predictive of future conversion?PubMed and Google Scholar databases were systematically searched. The primary inclusion criteria were to select studies that 1) were original research articles published in a peer-reviewed journal in the past 25years, 2) studied subjects at clinical high risk for psychosis or in the prodromal phase of illness, and 3) included examinations into verbal memory performance in those at clinical high risk for psychosis.64 articles were identified and screened for eligibility. The review included 34 studies investigating verbal memory impairment in clinical high risk individuals compared to controls. The average effect size of verbal learning total recall was .58, indicating a moderate level of impairment in verbal learning among individuals at clinical high risk for psychosis as compared to healthy controls. Of studies that predicted time to conversion, indices of memory, particularly declarative and verbal working memory, were especially predictive of future conversion. Finally, when examining investigations of the neural correlates of memory dysfunction in the clinical high risk state, findings suggest altered activation and functional connectivity among medial temporal lobe regions may underlie differences in memory performance between clinical high risk individuals and healthy controls.Findings to date strongly indicate that memory impairments are present during the premorbid phase of psychosis and that verbal memory impairment in particular is predictive of future conversion to psychosis. Evidence from fMRI studies is fairly consistent in showing greater activation of memory-related regions during retrieval among clinical high risk cases who convert, with less consistent evidence of altered functional connectivity in the encoding phase. These findings support the use of verbal learning and memory measures in the psychosis prediction and prevention field.

Oscillatory correlates of auditory working memory examined with human electrocorticography

This work examines how sounds are held in auditory working memory (AWM) in humans by examining oscillatory local field potentials (LFPs) in candidate brain regions. Previous fMRI studies by our group demonstrated blood oxygenation level-dependent (BOLD) response increases during maintenance in auditory cortex, inferior frontal cortex and the hippocampus using a paradigm with a delay period greater than 10s. The relationship between such BOLD changes and ensemble activity in different frequency bands is complex, and the long delay period raised the possibility that long-term memory mechanisms were engaged. Here we assessed LFPs in different frequency bands in six subjects with recordings from all candidate brain regions using a paradigm with a short delay period of 3 s. Sustained delay activity was demonstrated in all areas, with different patterns in the different areas. Enhancement in low frequency (delta) power and suppression across higher frequencies (beta/gamma) were demonstrated in primary auditory cortex in medial Heschl’s gyrus (HG) whilst non-primary cortex showed patterns of enhancement and suppression that altered at different levels of the auditory hierarchy from lateral HG to superior- and middle-temporal gyrus. Inferior frontal cortex showed increasing suppression with increasing frequency. The hippocampus and parahippocampal gyrus showed low frequency increases and high frequency decreases in oscillatory activity. This work demonstrates sustained activity patterns during AWM maintenance, with prominent low-frequency increases in medial temporal lobe regions.

The ratio of posterior-anterior medial temporal lobe volumes predicts source memory performance in healthy young adults.

A functional gradient has been proposed across the medial temporal lobes (MTL) such that the anterior MTL is thought to support processing of individual items (e.g., item memory and complex object perception), whereas the posterior MTL is thought to support item-context retrieval (e.g., source memory). Whereas functional imaging studies have provided evidence supporting this anatomical organization, results from structural analyses remain inconclusive. The current study examined the relationship between volume of MTL regions of interest (ROIs), and performance on a source memory task and a fine-grain complex object perception task, in healthy young adults (mean age = 21.5, range = 18-29). Using a semiautomated procedure, we segmented the parahippocampal and perirhinal cortices (PHC, PRC), posteromedial and anterolateral entorhinal cortices (pmERC, alERC), and posterior and anterior hippocampus (postHC, antHC) on high-resolution T2-weighted MRIs. Regional volumes were computed as proportions of intracranial volume, and as posterior-anterior volumetric ratios (PHC:PRC, pmERC:alERC, postHC:antHC). Partial-least squares regressions were applied to predict source and item memory, and perceptual discrimination accuracy, based on ROI and ratio volumes. In our ROI regressions, we found that postHC volume was positively correlated with a latent factor predicting source memory, and PRC and antHC volumes were negatively correlated to this latent factor. In our ratio regressions, we observed an effect relating the posterior-anterior distribution of gray matter across the MTL with source memory. Our results demonstrate differential associations between anterior and posterior MTL and source memory performance. Findings from this study highlight the importance of considering patterns of structure-behavior associations in the neurobiology of episodic memory.

Neural and behavioral correlates of episodic memory are associated with temporal discounting in older adults

When facing decisions involving trade-offs between smaller, sooner and larger, delayed rewards, people tend to discount the value of future rewards. There are substantial individual differences in this tendency toward temporal discounting, however. One neurocognitive system that may underlie these individual differences is episodic memory, given the overlap in the neural circuitry involved in imagining the future and remembering the past. Here we tested this hypothesis in older adults, including both those that were cognitively normal and those with amnestic mild cognitive impairment (MCI). We found that performance on neuropsychological measures of episodic memory retrieval was associated with temporal discounting, such that people with better memory discounted delayed rewards less. This relationship was specific to episodic memory and temporal discounting, since executive function (another cognitive ability) was unrelated to temporal discounting, and episodic memory was unrelated to risk tolerance (another decision-making preference). We also examined cortical thickness and volume in medial temporal lobe regions critical for episodic memory. Entorhinal cortical thickness was associated with reduced temporal discounting, with episodic memory performance partially mediating this association. The inclusion of MCI participants was critical to revealing these associations between episodic memory and entorhinal cortical thickness and temporal discounting. These effects were larger in the MCI group, reduced after controlling for MCI status, and statistically significant only when including MCI participants in analyses. Overall, these findings suggest that individual differences in temporal discounting are driven by episodic memory function, and that a decline in medial temporal lobe structural integrity may impact temporal discounting.

Tau PET imaging with 18F-PI-2620 in aging and neurodegenerative diseases.

In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD). Forty-nine participants were scanned with 18F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aβ+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum. SUVRs in target regions were relatively stable 60 to 90min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18F-PI-2620 were observed between HC and Aβ+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient. Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18F-PI-2620 in patients along the AD trajectory. This work confirms that 18F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

M161. NEURAL CHANGES INDUCED BY ELECTROCONVULSIVE THERAPY (ECT) IN SCHIZOPHRENIA PATIENTS: A SYSTEMATIC REVIEW

BackgroundDespite the remarkable progress of antipsychotic drugs, electroconvulsive therapy (ECT) remains a potent treatment option for schizophrenia. However, the underlying neural mechanism of ECT effect on schizophrenia remains unclear. For this reason, we reviewed literature which investigated structural and functional brain changes after ECT in schizophrenia patients.MethodsWe searched the PubMed, EMBASE, Cochrane Reviews database to search for eligible articles. Following medical subject headings (MeSH) terms were used: ECT AND schizophrenia AND (MRI OR MRS OR PET OR SPECT OR NIRS OR DTI).ResultsThirteen studies were eligible for the reviewing process. Of them, three studies investigated the effect of ECT upon volumetric changes of cerebral regions; 4 studies on the effect of ECT upon functional brain activities; three studies using magnetic resonance spectroscopy (MRS); and another three studies investigating blood flow changes. Medial temporal lobe (MTL) structures seemed to be increased after ECT sessions in schizophrenia patients, as in major depressive disorder (MDD) patients. Insula and left dorsolateral prefrontal cortex (DLFPC) is other potential neural substrates that might be disease specific for ECT induced changes in schizophrenia. Outcomes of functional imaging seemed to vary among studies, with divergent region of interests (ROI). MRS study results suggests the ratio of left prefrontal NAA/Cr might be increase after adequate ECT sessions. Studies investigating effect of ECT upon cerebral blood flow largely varied among studies with mixed results.DiscussionDespite the treatment effect of ECT in schizophrenia patients, there have been only a handful of studies investigating the biological mechanisms underlying ECT. Of them, the effect of ECT in schizophrenia seemed also to be mediated by structural volume increases in the MTL region (as in MDD), and the insula and left DLPFC might be other potential neural substrates of ECT effect in schizophrenia patients. Future studies are needed to validate the neural mechanisms that underlie the effect of ECT in schizophrenia, which might help to aid in tailoring treatment plans for refractory schizophrenia patients.

S164. HIPPOCAMPAL CONNECTIVITY IN YOUTH WITH SCHIZOPHRENIA: COMPARISON WITH PATIENTS WITH NMDA RECEPTOR ENCEPHALITIS AND HEALTHY VOLUNTEERS

BackgroundThe N-methyl-D-aspartate receptor (NMDAR) hypofunction model of schizophrenia suggests that dysfunction of these receptors could underlie the brain functional abnormalities characterising these patients. In NMDAR encephalitis (NMDARE), which holds clinical similarities with schizophrenia, autoantibodies target NMDARs, predominantly located in the hippocampal region, leading to disrupted glutamatergic transmission. One study so far has described abnormal connectivity between the medial temporal lobe and posterior default mode network regions in patients with NMDARE (Peer et al., 2017), however no study so far has examined brain functional correlates of schizophrenia and NMDARE comparatively.MethodsPatients with schizophrenia (N=16) and with NMDARE shortly after clinical stabilisation (N=15) were recruited within a tertiary setting, and compared with age and sex-matched healthy volunteers (N=20). All individuals were scanned with a 3T Siemens scanner including a functional resting state sequence, during which individuals were instructed to view a fixation cross. A seed-based analysis was performed using a spherical seed of 4mm located in the left hippocampus (MNI coordinates x =-32, y=-24, x=-14). Only grey matter voxels were considered to obtain the seed average signal. BOLD signal was preprocessed including slice timing, motion correction, spatial smoothing, and frequency filtering, and regressed taken into account movement parameters (rigid transformation, frame displacement, and DVARS). Statistics was performed between the correlation maps including age and sex as covariates. Family-wise error (FWE) was used to correct for multiple comparisons.ResultsSeed to voxel analyses revealed connectivity between the seed and the bilateral thalamus, parahippocampus, precuneus, posterior cingulate, right hippocampus and lateral temporal regions (threshold Fisher’s z > 0.28). We first examined differences in connectivity between both patient groups combined and healthy volunteers, which revealed greater connectivity in patients than in controls between the left hippocampus and the left inferior parietal, postcentral and posterior cingulate gyri (pFWE< 0.05). When examining patient groups individually, patients with schizophrenia continued to exhibit significantly greater connectivity between the left hippocampus and left inferior parietal and postcentral region (pFWE< 0.05) and at near trend level in the posterior cingulate (pFWE= 0.15). NMDARE patients also presented near trend level increased connectivity in the posterior cingulate and postcentral gyri (pFWE= 0.10). There were no differences in functional connectivity of the left hippocampus between patients with schizophrenia and with NMDARE.DiscussionTo our knowledge, this is the first study to compare patients with schizophrenia with patients with NMDARE using measures of brain function. We found that, for both conditions, the left hippocampus showed greater connectivity with areas belonging to the posterior default mode network. Connectivity between these regions has been associated with psychotic symptoms in schizophrenia (Lefebvre et al., 2016). Our findings suggest that this alteration could also underlie neuropsychiatric symptoms in NMDARE, and provides further evidence that NMDAR dysfunction may underpin the pathophysiology of schizophrenia.

Patterns of longitudinal cortical atrophy over 3 years in empirically derived MCI subtypes

We previously identified 4 empirically derived mild cognitive impairment (MCI) subtypes via cluster analysis within the Alzheimer's Disease Neuroimaging Initiative (ADNI) and demonstrated high correspondence between patterns of cortical thinning at baseline and each cognitive subtype. We aimed to determine whether our MCI subtypes demonstrate unique longitudinal atrophy patterns. ADNI participants (295 with MCI and 134 cognitively normal [CN]) underwent annual structural MRI and neuropsychological assessments. General linear modeling compared vertex-wise differences in cortical atrophy rates between each MCI subtype and the CN group. Linear mixed models examined trajectories of cortical atrophy over 3 years within lobar regions of interest. Compared to the CN group, those with amnestic MCI (memory deficit) initially demonstrated greater atrophy rates within medial temporal lobe regions that became more widespread over time. Those with dysnomic/amnestic MCI (naming/memory deficits) showed greater atrophy rates largely localized to temporal lobe regions. The mixed MCI (impairment in all cognitive domains) group showed greater atrophy rates in widespread regions at all time points. The cluster-derived normal group, who had intact neuropsychological performance and normal cortical thickness at baseline despite their MCI diagnosis via conventional diagnostic criteria, continued to show normal cognition and minimal cortical atrophy over 3 years. ADNI's purported amnestic MCI sample produced more refined cognitive subtypes with unique longitudinal cortical atrophy rates. These novel MCI subtypes reliably reflect underlying atrophy, reduce false-positive diagnostic errors, and improve prediction of clinical course. Such improvements have implications for the selection of participants for clinical trials and for providing more precise risk assessment for individuals diagnosed with MCI.

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

It is unclear how different proteinopathies (tau, transactive response DNA-binding protein 43 [TDP-43], amyloid β [Aβ], and α-synuclein) contribute to atrophy within medial temporal lobe (MTL) subregions in Alzheimer's disease (AD). We utilized antemortem structural magnetic resonance imaging (MRI) data to measure MTL substructures and examined the relative contribution of tau, TDP-43, Aβ, 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. 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). 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.

Medial temporal lobe connectivity and its associations with cognition in early Alzheimer's disease.

Human episodic memory critically depends on subregions of the medial temporal lobe, which are part of functional brain systems such as the anterior-temporal and the posterior-medial system. Here we analysed how Alzheimer's pathology affects functional connectivity within these systems. Data from 256 amyloid-β-negative cognitively unimpaired, 103 amyloid-β-positive cognitively unimpaired, and 83 amyloid-β-positive individuals with mild cognitive impairment were analysed. Amyloid-β and tau pathology were measured using the CSF amyloid-β42/40 ratio and phosphorylated tau, respectively. We found that amyloid-β-positive cognitively unimpaired individuals were mainly characterized by decreased functional connectivity between the medial temporal lobe and regions in the anterior-temporal system, most prominently between left perirhinal/entorhinal cortices and medial prefrontal cortex. Furthermore, correlation analysis in this group revealed decreasing functional connectivity between bilateral perirhinal/entorhinal cortices, anterior hippocampus and posterior-medial regions with increasing levels of phosphorylated tau. The amyloid-β-positive individuals with mild cognitive impairment mostly exhibited reduced connectivity between the medial temporal lobe and posterior-medial regions, predominantly between the anterior hippocampus and posterior cingulate cortex. In addition, they showed hyperconnectivity within the medial temporal lobe and its immediate proximity. Lower medial temporal-cortical functional connectivity networks resulting from the group comparisons of cognitively unimpaired individuals were associated with reduced memory performance and more rapid longitudinal memory decline as shown by linear mixed-effects regression analysis. Finally, we found that reduced medial temporal-cortical connectivity in mildly cognitively impaired individuals was related to reduced entorhinal thickness and white matter integrity of the parahippocampal cingulum and the fornix. No such relationships were found in cognitively unimpaired individuals. In conclusion, our findings show that the earliest changes in preclinical Alzheimer's disease might involve decreased connectivity within the anterior-temporal system, and early changes in connectivity might be related to memory impairment, but not to structural changes. With disease progression and increased tau pathology, medial temporal functional connectivity with posterior-medial regions seems to be increasingly impaired. In individuals with mild cognitive impairment, reduced functional connectivity is associated with structural brain changes as well as the emergence of locally increased connectivity patterns. Thus, functional connectivity between the medial temporal lobe and the anterior-temporal and posterior-medial system could serve as stage-specific functional markers in early Alzheimer's disease.

Medial temporal lobe regions mediate complex visual discriminations for both objects and scenes: A process-based view.

Debate continues regarding the role of medial temporal lobe regions in object and scene processing. Considerable evidence indicates that the perirhinal cortex (PRC) plays an important role in the perception of objects-namely, in disambiguating complex objects that share conjunctions of features. These findings support a content-specific view of medial temporal lobe functioning in which PRC is critically important for processing complex objects, while the parahippocampal cortex (PHC) and hippocampus (HC) may be selectively engaged during scene processing. However, emerging evidence from both animal and human studies suggest that the PRC is sensitive to spatial configural information as well as object information. In this fMRI study, we observed preliminary evidence for BOLD activation in the PRC during a complex visual discrimination task for objects and scenes, as well as robust activation for both stimulus types in PHC and HC. The results are discussed in light of a recent process-based model of medial temporal lobe functioning.

Interaction of APOE, cerebral blood flow, and cortical thickness in the entorhinal cortex predicts memory decline

The ε4 allele of the apolipoprotein E (APOE)gene, a risk factor for cognitive decline, is associated with alterations in medial temporal lobe (MTL) structure and function, yet little research has been dedicated to understanding how these alterations might interact to negatively impact cognition. To bridge this gap, the present study employed linear regression models to determine the extent to which APOE genotype (ε4+, ε4-) modifies interactive effects of baseline arterial spin labeling MRI-measured cerebral blood flow (CBF) and FreeSurfer-derived cortical thickness/volume (CT/Vo) in two MTL regions of interest (entorhinal cortex, hippocampus) on memory change in 98 older adults who were cognitively normal at baseline. Baseline entorhinal CBF was positively associated with memory change, but only among ε4 carriers with lower entorhinal CT. Similarly, baseline entorhinal CT was positively associated with memory change, but only among ε4 carriers with lower entorhinal CBF. Findings suggest that APOE ε4 carriers may experience concomitant alterations in neurovascular function and morphology in the MTL that interact to negatively affect cognition prior to the onset of overt clinical symptoms. Results also suggest the presence of distinct multimodal neural signatures in the entorhinal cortex that may signal relative risk for cognitive decline among this group, perhaps reflecting different stages of cerebrovascular compensation (early effective vs. later ineffective).

Alpha Rhythms Reveal When and Where Item and Associative Memories Are Retrieved.

Memories for past experiences can range from vague recognition to full-blown recall of associated details. Electroencephalography has shown that recall signals unfold a few hundred milliseconds after simple recognition, but has only provided limited insights into the underlying brain networks. Functional magnetic resonance imaging (fMRI) has revealed a “core recollection network” (CRN) centered on posterior parietal and medial temporal lobe regions, but the temporal dynamics of these regions during retrieval remain largely unknown. Here we used Magnetoencephalography in a memory paradigm assessing correct rejection (CR) of lures, item recognition (IR) and associative recall (AR) in human participants of both sexes. We found that power decreases in the alpha frequency band (10–12 Hz) systematically track different mnemonic outcomes in both time and space: Over left posterior sensors, alpha power decreased in a stepwise fashion from 500 ms onward, first from CR to IR and then from IR to AR. When projecting alpha power into source space, the CRN known from fMRI studies emerged, including posterior parietal cortex (PPC) and hippocampus. While PPC showed a monotonic change across conditions, hippocampal effects were specific to recall. These region-specific effects were corroborated by a separate fMRI dataset. Importantly, alpha power time courses revealed a temporal dissociation between item and associative memory in hippocampus and PPC, with earlier AR effects in hippocampus. Our data thus link engagement of the CRN to the temporal dynamics of episodic memory and highlight the role of alpha rhythms in revealing when and where different types of memories are retrieved.SIGNIFICANCE STATEMENT Our ability to remember ranges from the vague feeling of familiarity to vivid recollection of associated details. Scientific understanding of episodic memory thus far relied upon separate lines of research focusing on either temporal (via electroencephalography) or spatial (via functional magnetic resonance imaging) dimensions. However, both techniques have limitations that have hindered understanding of when and where memories are retrieved. Capitalizing on the enhanced temporal and spatial resolution of magnetoencephalography, we show that changes in alpha power reveal both when and where different types of memory are retrieved. Having access to the temporal and spatial characteristics of successful retrieval provided new insights into the cross-regional dynamics in the hippocampus and parietal cortex.

Understanding the neural basis of episodic amnesia in logopenic progressive aphasia: A multimodal neuroimaging study

Logopenic progressive aphasia (LPA) is a neurodegenerative disorder characterised by profound naming and sentence repetition disturbances, attributable to disproportionately left-sided temporo-parietal atrophy. Accumulating evidence suggests, in addition to language impairments, the presence of stark verbal and nonverbal episodic memory dysfunction in LPA. The neurocognitive bases of such impairments, however, remain to be clarified. Here, we characterised episodic memory disruption and its corresponding grey and white matter correlates in the LPA syndrome. Nineteen LPA patients were contrasted with 23 matched typical Alzheimer's disease (AD) patients and 31 healthy Controls on standardized verbal and nonverbal episodic delayed recall measures. Participants further underwent structural magnetic resonance and diffusion-weighted imaging. Significant verbal memory deficits were evident in both patient groups, with LPA patients performing at an intermediate level to AD and Controls. For nonverbal memory, however, LPA performance was indistinguishable from that of AD, with both groups displaying marked impairments relative to Controls. Whole-brain voxel-based morphometry analyses revealed significant left temporo-parietal and left hippocampal atrophy in the LPA group. Covariate analyses showed that verbal and nonverbal amnesia in LPA correlated with grey matter integrity of bilateral frontoparietal and left medial temporal lobe regions. Notably, the common regions underpinning verbal and nonverbal memory dysfunction in LPA were the left orbitofrontal cortex and bilateral angular gyri in the inferior parietal cortex. The bilateral angular gyri, along with prefrontal and hippocampal regions further emerged as disease-general correlates of verbal and nonverbal memory performance. Alterations in mean diffusivity in structural connections between the left angular gyrus and medial temporal lobes were further associated with verbal memory performance in all participants. Our findings reveal, for the first time, the presence of pervasive memory impairments in LPA mediated by degeneration of a distributed prefrontal-hippocampal-parietal network, and disrupted parieto-hippocampal structural connectivity.

Amyloid and tau imaging biomarkers explain cognitive decline from late middle-age.

This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.

In vivo measures of tau burden are associated with atrophy in early Braak stage medial temporal lobe regions in amyloid-negative individuals

IntroductionIt is unclear the degree to which tau pathology in the medial temporal lobe (MTL) measured by 18F-flortaucipir positron emission tomography relates to MTL subregional atrophy and whether this relationship differs between amyloid-β–positive and amyloid-β–negative individuals. MethodsWe analyzed correlation of MTL 18F-flortaucipir uptake with MTL subregional atrophy measured with high-resolution magnetic resonance imaging in a region of interest and regional thickness analysis and determined the relationship between memory performance and positron emission tomography and magnetic resonance imaging measures. ResultsBoth groups showed strong correlations between 18F-flortaucipir uptake and atrophy, with similar spatial patterns. Effects in the rhinal cortex recapitulated Braak staging. Correlations of memory recall with atrophy and tracer uptake were observed. DiscussionCorrelation patterns between tau burden and atrophy in the amyloid-β–negative group mimicking early Braak stages suggests that 18F-flortaucipir is sensitive to tau pathology in primary age-related tauopathy. Correlations of imaging measures with memory performance indicate that this pathology is associated with poorer cognition.

Compensatory Hippocampal Recruitment Supports Preserved Episodic Memory in Autism Spectrum Disorder

BackgroundThe degree to which individuals with autism spectrum disorder (ASD) evidence impairments in episodic memory relative to their typically developing (TD) counterparts remains unclear. According to a prominent view, ASD is associated with deficits in encoding associations between items and recollecting precise context details. Here, we evaluated behavioral and neural evidence for this impaired relational binding hypothesis using a task involving relational encoding and recollection during functional magnetic resonance imaging. MethodsAdolescents and young adults (nASD = 47, nTD = 60) performed the Relational and Item-Specific Encoding task during functional magnetic resonance imaging, including item and associative recognition testing. We modeled functional recruitment within the medial temporal lobes (MTLs), and connectivity between MTL and the posterior medial (PM) network thought to underlie relational memory. The impaired relational binding model would predict a behavioral deficit driven by aberrant recruitment and connectivity of MTL and the PM network. ResultsThe ASD and TD groups showed indistinguishable item and associative recognition performance. During relational encoding, the ASD group demonstrated increased hippocampal recruitment, and decreased connectivity between MTL and PM regions relative to the TD group. Within ASD, hippocampal recruitment and MTL-PM connectivity were inversely correlated. ConclusionsThe lack of a behavioral deficit in ASD does not support the impaired relational binding hypothesis. Instead, the current data suggest that increased recruitment of the hippocampus compensates for decreased MTL-PM connectivity to support preserved episodic memory in ASD. These findings suggest a compensatory neurodevelopmental mechanism that may support preserved cognitive domains in ASD: local hyperrecruitment may offset connectivity aberrations in individuals with ASD relative to TD subjects.