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PurposeIn vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD).MethodsForty-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.ResultsSUVRs in target regions were relatively stable 60 to 90 min 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.ConclusionPreliminary 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.

Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function1. However, little is known about the contribution of the adaptive immune response in Alzheimer's disease2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer's disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer's disease that consists of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8+ TEMRA cells in the cerebrospinal fluid of patients with Alzheimer's disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer's disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer's disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.

Autobiographical remembering can depend on two forms of memory: episodic (event) memory and autobiographical semantic memory (remembering personally relevant semantic knowledge, independent of recalling a specific experience). There is debate about the degree to which the neural signals that support episodic recollection relate to or build upon autobiographical semantic remembering. Pooling data from two fMRI studies of memory for real-world personal events, we investigated whether medial temporal lobe (MTL) and parietal subregions contribute to autobiographical episodic and semantic remembering. During scanning, participants made memory judgments about photograph sequences depicting past events from their life or from others' lives, and indicated whether memory was based on episodic or semantic knowledge. Results revealed several distinct functional patterns: activity in most MTL subregions was selectively associated with autobiographical episodic memory; the hippocampal tail, superior parietal lobule, and intraparietal sulcus were similarly engaged when memory was based on retrieval of an autobiographical episode or autobiographical semantic knowledge; and angular gyrus demonstrated a graded pattern, with activity declining from autobiographical recollection to autobiographical semantic remembering to correct rejections of novel events. Collectively, our data offer insights into MTL and parietal cortex functional organization, and elucidate circuitry that supports different forms of real-world autobiographical memory.

For the human brain to operate, populations of neurons across anatomical structures must coordinate their activity within milliseconds. To date, our understanding of such interactions has remained limited. We recorded directly from the hippocampus (HPC), posteromedial cortex (PMC), ventromedial/orbital prefrontal cortex (OFC), and the anterior nuclei of the thalamus (ANT) during two experiments of autobiographical memory processing that are known from decades of neuroimaging work to coactivate these regions. In 31 patients implanted with intracranial electrodes, we found that the presentation of memory retrieval cues elicited a significant increase of low frequency (LF < 6 Hz) activity followed by cross-regional phase coherence of this LF activity before select populations of neurons within each of the four regions increased high-frequency (HF > 70 Hz) activity. The power of HF activity was modulated by memory content, and its onset followed a specific temporal order of ANT→HPC/PMC→OFC. Further, we probed cross-regional causal effective interactions with repeated electrical pulses and found that HPC stimulations cause the greatest increase in LF-phase coherence across all regions, whereas the stimulation of any region caused the greatest LF-phase coherence between that particular region and ANT. These observations support the role of the ANT in gating, and the HPC in synchronizing, the activity of cortical midline structures when humans retrieve self-relevant memories of their past. Our findings offer a fresh perspective, with high temporal fidelity, about the dynamic signaling and underlying causal connections among distant regions when the brain is actively involved in retrieving self-referential memories from the past. [ABSTRACT FROM AUTHOR]

Extant neuroimaging data implicate frontoparietal and medial-temporal lobe regions in episodic retrieval, and the specific pattern of activity within and across these regions is diagnostic of an individual's subjective mnemonic experience. For example, in laboratory-based paradigms, memories for recently encoded faces can be accurately decoded from single-trial fMRI patterns [Uncapher, M. R., Boyd-Meredith, J. T., Chow, T. E., Rissman, J., & Wagner, A. D. Goal-directed modulation of neural memory patterns: Implications for fMRI-based memory detection. Journal of Neuroscience, 35, 8531-8545, 2015; Rissman, J., Greely, H. T., & Wagner, A. D. Detecting individual memories through the neural decoding of memory states and past experience. Proceedings of the National Academy of Sciences, U.S.A., 107, 9849-9854, 2010]. Here, we investigated the neural patterns underlying memory for real-world autobiographical events, probed at 1- to 3-week retention intervals as well as whether distinct patterns are associated with different subjective memory states. For 3 weeks, participants (n = 16) wore digital cameras that captured photographs of their daily activities. One week later, they were scanned while making memory judgments about sequences of photos depicting events from their own lives or events captured by the cameras of others. Whole-brain multivoxel pattern analysis achieved near-perfect accuracy at distinguishing correctly recognized events from correctly rejected novel events, and decoding performance did not significantly vary with retention interval. Multivoxel pattern classifiers also differentiated recollection from familiarity and reliably decoded the subjective strength of recollection, of familiarity, or of novelty. Classification-based brain maps revealed dissociable neural signatures of these mnemonic states, with activity patterns in hippocampus, medial PFC, and ventral parietal cortex being particularly diagnostic of recollection. Finally, a classifier trained on previously acquired laboratory-based memory data achieved reliable decoding of autobiographical memory states. We discuss the implications for neuroscientific accounts of episodic retrieval and comment on the potential forensic use of fMRI for probing experiential knowledge.

Remembering a past event elicits distributed neural patterns that can be distinguished from patterns elicited when encountering novel information. These differing patterns can be decoded with relatively high diagnostic accuracy for individual memories using multivoxel pattern analysis (MVPA) of fMRI data. Brain-based memory detection--if valid and reliable--would have clear utility beyond the domain of cognitive neuroscience, in the realm of law, marketing, and beyond. However, a significant boundary condition on memory decoding validity may be the deployment of "countermeasures": strategies used to mask memory signals. Here we tested the vulnerability of fMRI-based memory detection to countermeasures, using a paradigm that bears resemblance to eyewitness identification. Participants were scanned while performing two tasks on previously studied and novel faces: (1) a standard recognition memory task; and (2) a task wherein they attempted to conceal their true memory state. Univariate analyses revealed that participants were able to strategically modulate neural responses, averaged across trials, in regions implicated in memory retrieval, including the hippocampus and angular gyrus. Moreover, regions associated with goal-directed shifts of attention and thought substitution supported memory concealment, and those associated with memory generation supported novelty concealment. Critically, whereas MVPA enabled reliable classification of memory states when participants reported memory truthfully, the ability to decode memory on individual trials was compromised, even reversing, during attempts to conceal memory. Together, these findings demonstrate that strategic goal states can be deployed to mask memory-related neural patterns and foil memory decoding technology, placing a significant boundary condition on their real-world utility.

ObjectiveAn increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol.MethodMRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement.ResultsThe differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail.ConclusionsThe combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

Episodic recollection entails the conscious remembrance of event details associated with previously encountered stimuli. Recollection depends on both the establishment of cortical representations of event features during stimulus encoding and the cortical reinstatement of these representations at retrieval. Here, we used multivoxel pattern analyses of functional magnetic resonance imaging data to examine how cortical and hippocampal activity at encoding and retrieval drive recollective memory decisions. During encoding, words were associated with face or scene source contexts. At retrieval, subjects were cued to recollect the source associate of each presented word. Neurally derived estimates of encoding strength and pattern reinstatement in occipitotemporal cortex were computed for each encoding and retrieval trial, respectively. Analyses demonstrated that (1) cortical encoding strength predicted subsequent memory accuracy and reaction time, (2) encoding strength predicted encoding-phase hippocampal activity, and (3) encoding strength and retrieval-phase hippocampal activity predicted the magnitude of cortical reinstatement. Path analyses further indicated that cortical reinstatement partially mediated both the effect of cortical encoding strength and the effect of retrieval-phase hippocampal activity on subsequent source memory performance. Taken together, these results indicate that memory-guided decisions are driven in part by a pathway leading from hippocampally linked cortical encoding of event attributes to hippocampally linked cortical reinstatement at retrieval.

Motivated by evidence that the dentate gyrus differentially mediates the pattern separation (PS) component of declarative memory function and that dentate gyrus harbors molecular and cellular pathologies in schizophrenia, we examined whether PS performance is altered in volunteers with schizophrenia (SZV) relative to healthy volunteers (HV). In groups of well-characterized SZV (n=14) and HV (n=15), we contrasted performance on the Behavioral Pattern Separation (BPS) Task, acquiring two outcome measures, a PS parameter and a Recognition Memory (RM) parameter, as well as specific recognition data by stimulus type. The SZVs showed a significant decrement in PS performance relative to HV (mean ± SEM, SZV: 3.1 ± 2.7%; HV: 17.1 ± 5.8%; p=0.039, d'=0.86); whereas SZV and HV did not significantly differ in RM performance (SZV: 50.1 ± 8.1%; HV: 59.3 ± 5.5%; p=0.350, d'=0.36). Moreover, the SZVs showed a selective defect in correctly identifying similar lure items (SZV: 24.0 ± 3.7%; HV: 41.2 ± 4.6%; p

Cognitive control allows stimulus-response processing to be aligned with internal goals and is thus central to intelligent, purposeful behavior. Control is thought to depend in part on the active representation of task information in prefrontal cortex (PFC), which provides a source of contextual bias on perception, decision making, and action. In the present study, we investigated the organization, influences, and consequences of context representation as human subjects performed a cued sorting task that required them to flexibly judge the relationship between pairs of multivalent stimuli. Using a connectivity-based parcellation of PFC and multivariate decoding analyses, we determined that context is specifically and transiently represented in a region spanning the inferior frontal sulcus during context-dependent decision making. We also found strong evidence that decision context is represented within the intraparietal sulcus, an area previously shown to be functionally networked with the inferior frontal sulcus at rest and during task performance. Rule-guided allocation of attention to different stimulus dimensions produced discriminable patterns of activation in visual cortex, providing a signature of top-down bias over perception. Furthermore, demands on cognitive control arising from the task structure modulated context representation, which was found to be strongest after a shift in task rules. When context representation in frontoparietal areas increased in strength, as measured by the discriminability of high-dimensional activation patterns, the bias on attended stimulus features was enhanced. These results provide novel evidence that illuminates the mechanisms by which humans flexibly guide behavior in complex environments.

While attention is critical for event memory, debate has arisen regarding the extent to which posterior parietal cortex (PPC) activation during episodic retrieval reflects engagement of PPC-mediated mechanisms of attention. Here, we directly examined the relationship between attention and memory, within and across subjects, using functional magnetic resonance imaging attention-mapping and episodic retrieval paradigms. During retrieval, 4 functionally dissociable PPC regions were identified. Specifically, 2 PPC regions positively tracked retrieval outcomes: lateral intraparietal sulcus (latIPS) indexed graded item memory strength, whereas angular gyrus (AnG) tracked recollection. By contrast, 2 other PPC regions demonstrated nonmonotonic relationships with retrieval: superior parietal lobule (SPL) tracked retrieval reaction time, consistent with a graded engagement of top-down attention, whereas temporoparietal junction displayed a complex pattern of below-baseline retrieval activity, perhaps reflecting disengagement of bottom-up attention. Analyses of retrieval effects in PPC topographic spatial attention maps (IPS0-IPS5; SPL1) revealed that IPS5 and SPL1 exhibited a nonmonotonic relationship with retrieval outcomes resembling that in the SPL region, further suggesting that SPL activation during retrieval reflects top-down attention. While demands on PPC attention mechanisms vary during retrieval attempts, the present functional parcellation of PPC indicates that 2 additional mechanisms (mediated by latIPS and AnG) positively track retrieval outcomes.

Upon retrieval, memories can become susceptible to meaningful events, such as stress. Post-retrieval memory changes may be attributed to an alteration of the original memory trace during reactivation-dependent reconsolidation or, alternatively, to the modification of retrieval-related memory traces that impact future remembering. Hence, how post-retrieval memory changes emerge in the human brain is unknown. In a 3-day functional magnetic resonance imaging study, we show that post-retrieval stress impairs subsequent memory depending on the strength of neural reinstatement of the original memory trace during reactivation, driven by the hippocampus and its cross-talk with neocortical representation areas. Comparison of neural patterns during immediate and final memory testing further revealed that successful retrieval was linked to pattern-dissimilarity in controls, suggesting the use of a different trace, whereas stressed participants relied on the original memory representation. These representation changes were again dependent on neocortical reinstatement during reactivation. Our findings show disruptive stress effects on the consolidation of retrieval-related memory traces that support future remembering. [ABSTRACT FROM AUTHOR]

INTRODUCTION: In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults. METHODS: We constructed a protein co‐expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically‐relevant outcomes. RESULTS: We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p‐tau181 (M4: β = 2.44, p < 0.001, M7: β = 2.57, p < 0.001) and executive function performance (M4: β = −2.00, p = 0.005, M7: β = −2.39, p < 0.001). DISCUSSION: In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post‐translational modifications for early cognitive and pathological changes. [ABSTRACT FROM AUTHOR]

Remembering an event from the past is often complicated by the fact that our memories are cluttered with similar events. Though competition is a fundamental part of remembering, there is little evidence of how mnemonic competition is neurally represented. Here, we assessed whether competition between visual memories is captured in the relative degree to which target vs. competing memories are reactivated within the ventral occipitotemporal cortex (VOTC). To assess reactivation, we used multivoxel pattern analysis of fMRI data, quantifying the degree to which retrieval events elicited patterns of neural activity that matched those elicited during encoding. Consistent with recent evidence, we found that retrieval of visual memories was associated with robust VOTC reactivation and that the degree of reactivation scaled with behavioral expressions of target memory retrieval. Critically, competitive remembering was associated with more ambiguous patterns of VOTC reactivation, putatively reflecting simultaneous reactivation of target and competing memories. Indeed, the more weakly that target memories were reactivated, the more likely that competing memories were later remembered. Moreover, when VOTC reactivation indicated that conflict between target and competing memories was high, frontoparietal mechanisms were markedly engaged, revealing specific neural mechanisms that tracked competing mnemonic evidence. Together, these findings provide unique evidence that neural reactivation captures competition between individual memories, providing insight into how well target memories are retrieved in the present and how likely competing memories will be remembered in the future.