Search

We investigated whether the impact of tau-pathology on memory performance and on hippocampal/medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF (92 cognitively unimpaired, 100 experiencing subjective cognitive decline and 43 with mild cognitive impairment). Presence (A+) and absence (A−) of amyloid pathology was defined by CSF amyloid-β42 (Aβ42) levels. Free recall performance in the Free and Cued Selective Reminding Test, scene recognition memory accuracy and hippocampal/medial temporal functional MRI novelty responses to scene images were related to CSF total-tau and phospho-tau levels separately for A+ and A− individuals. We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aβ42 levels. Subgroup analyses showed that these relationships were only present in A+ and remained stable when very high levels of tau (>700 pg/ml) and phospho-tau (>100 pg/ml) were excluded. These relationships were significant with diagnosis, age, education, sex, assessment site and Aβ42 levels as covariates. They also remained significant after propensity score based matching of phospho-tau levels across A+ and A− groups. After classifying this matched sample for phospho-tau pathology (T−/T+), individuals with A+/T+ were significantly more memory-impaired than A−/T+ despite the fact that both groups had the same amount of phospho-tau pathology. ApoE status (presence of the E4 allele), a known genetic risk factor for Alzheimer’s disease, did not mediate the relationship between tau pathology and hippocampal function and memory performance. Thus, our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment. This raises the possibility that in the predementia stage of Alzheimer’s disease, removing the negative impact of amyloid pathology could improve memory and hippocampal function even if the amount of tau-pathology in CSF is not changed, whereas reducing increased CSF tau-pathology in amyloid-negative individuals may not proportionally improve memory function.

The hippocampus is one of the most studied neuroanatomical structures due to its involvement in attention, learning, and memory as well as its atrophy in ageing, neurological, and psychiatric diseases. Hippocampal shape changes, however, are complex and cannot be fully characterized by a single summary metric such as hippocampal volume as determined from MR images. In this work, we propose an automated, geometry-based approach for the unfolding, point-wise correspondence, and local analysis of hippocampal shape features such as thickness and curvature. Starting from an automated segmentation of hippocampal subfields, we create a 3D tetrahedral mesh model as well as a 3D intrinsic coordinate system of the hippocampal body. From this coordinate system, we derive local curvature and thickness estimates as well as a 2D sheet for hippocampal unfolding. We evaluate the performance of our algorithm with a series of experiments to quantify neurodegenerative changes in Mild Cognitive Impairment and Alzheimer's disease dementia. We find that hippocampal thickness estimates detect known differences between clinical groups and can determine the location of these effects on the hippocampal sheet. Further, thickness estimates improve classification of clinical groups and cognitively unimpaired controls when added as an additional predictor. Comparable results are obtained with different datasets and segmentation algorithms. Taken together, we replicate canonical findings on hippocampal volume/shape changes in dementia, extend them by gaining insight into their spatial localization on the hippocampal sheet, and provide additional, complementary information beyond traditional measures. We provide a new set of sensitive processing and analysis tools for the analysis of hippocampal geometry that allows comparisons across studies without relying on image registration or requiring manual intervention., Comment: Updated to journal publication

Amyloid-beta (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe (MTL). However, there is evidence that age-related Aβ-independent tau pathology is present outside the MTL (Kaufman et al., Acta Neuropathol, 2018). We examine tau deposition determined by positron emission tomography (PET) in regions typically involved earlier/later in AD and downstream effects on neurodegeneration and cognition in cognitively unimpaired older adults and a low-Aβ subgroup.MethodsWe included 488 adults (40-91 years; low-Aβ: n=355, 65.2±11.5 years) from the BioFINDER-2 study. MTL volumes (dentate gyrus, subiculum (SUB), cornu ammonis 1) and thickness (entorhinal cortex, Brodmann areas (BA)35/36, and parahippocampal cortex) were obtained, using Automated Segmentation for Hippocampal Subfields packages for T1- and T2-weighted magnetic resonance images. Thickness of early/late neocortical AD-regions (anterior cingulate, precuneus/posterior cingulate (PPC), orbitofrontal, inferior parietal cortex; and middle frontal, lateral occipital, and precentral/postcentral gyrus) was determined using FreeSurfer. [18F]RO948- and [18F]flutemetamol-PET standardized uptake value ratios (SUVRs) were calculated for local tau and global/local Aβ. Aβ status was determined using Aβ-PET or cerebrospinal fluid Aβ-42/40 ratio. Global cognition was measured using delayed word-list recall, trail making test B, and animal fluency.ResultsIncreasing age was associated with higher tau-PET SUVRs primarily in MTL/frontal/parietal regions. A significant association between age and local tau-PET remained even when including Aβ-PET as a mediator (Fig. 1).Age and local tau-PET, but not Aβ-PET, where negatively associated with structure in most examined regions (Figs. 2-3). Age-structure associations were serially mediated via tau-PET in regions with early AD pathology (SUB/BA35/PPC). Also, in the low-Aβ subgroup, tau-PET mediated the age-structure (SUB/BA35/PPC) associations (Fig. 3D). Finally, the age-global cognition relationship was serially mediated via MTL tau-PET and subiculum volume, even when including global Aβ-PET as additional mediator (Fig. 4).ConclusionWe observe partially Aβ-independent associations between age and tau-PET signal across the neocortex. Interestingly, partially Aβ-independent tau-PET signal appears to mediate the age-structure associations in and outside the MTL (PPC), also in the low-Aβ group, and the age-MTL structure-cognition associations. This potentially provides in vivo support for Primary Age-related Tauopathy downstream effects on structure, beyond the MTL, and cognition.

Remote and unsupervised cognitive testing using smartphones may improve sensitivity to detect preclinical Alzheimer’s disease (AD). In particular, cognitive testing at-home enables the evaluation of the potentially more sensitive long-term delayed memory retrieval, which is commonly not feasible in a clinical setting.MethodHere, we investigated the association between remote and unsupervised smartphone-based cognitive assessments and in-clinic cognitive measurement in older participants (CDR = 0, MMSE = 29.2, age = 77). The sample (non-demented at age 70) was derived from the Swedish population-based Gothenburg H70 Birth Cohort Studies. In a subsample of participants, the retrospective correlation with cerebrospinal fluid (CSF) biomarkers analyzed at age 70 was further explored. To this point, 177 H70-participants have consented and were enrolled into the smartphone sub-study. They completed an “Object-in-Room Recall Test“ (ORR) remotely and unsupervised using own mobile devices, and the recall session was initiated 24 hours after the initial learning phase. Available previously assessed CSF measures included the Aβ42/Aβ40-ratio, t-tau, p-tau, neurofilament light (NFL), and neurogranin, available in-clinic cognitive tests included the Rey Auditory Verbal Learning Test (RAVLT), Semantic Fluency, Digit-Symbol-Coding, and Mini Mental State Examination. The above-mentioned cognitive tests were used to derive the Preclinical Alzheimer's Cognitive Composite (PACC5), a composite designed to be sensitive to cognitive change in preclinical AD. All associations were examined using Pearson correlation coefficient.ResultPreliminary analyses in a subset of participants yielded relatively strong positive correlations between PACC5 (R = .50, p

International audience; Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images.

Cortical processing streams for item and contextual information come together in the entorhinal-hippocampal circuitry. Various evidence suggest that information-specific pathways organize the cortical – entorhinal interaction and the circuitry’s inner communication along the transversal axis. Here, we leveraged ultra-high field functional imaging and advance Maass, Berron et al. (2015) who report two functional routes segregating the entorhinal cortex (EC) and subiculum. Our data show specific scene processing in the functionally connected posterior-medial EC and distal subiculum. The regions of another route, that connects the anterior-lateral EC and a newly identified retrosplenial-based anterior-medial EC subregion with the CA1/subiculum border, process object and scene information similarly. Our results support topographical information flow in human entorhinal-hippocampal subregions with organized convergence of cortical processing streams and a unique route for contextual information. They characterize the functional organization of the circuitry and underpin its central role in memory function and pathological decline.

INTRODUCTIONMobile app-based unsupervised monitoring of cognition holds the promise to facilitate case-finding in clinical care and the individual detection of cognitive impairment in clinical and research settings. In the context of Alzheimer’s disease, this is particularly relevant for patients who seek medical advice due to memory complaints.OBJECTIVEWe developed a Remote Digital Memory Composite score from an unsupervised remote and mobile cognitive assessment battery focused on episodic memory and long-term recall and assessed its construct validity using a neuropsychological composite score for early cognitive impairment in Alzheimer’s disease, the Preclinical Alzheimer’s Cognitive Composite (PACC5). We also assessed the test-retest reliability of the Remote Digital Memory Composite score across two independent test sessions. Finally, we assessed the diagnostic accuracy of the remote and unsupervised cognitive assessment battery when predicting PACC5-based cognitive impairment in a memory clinic sample and healthy controls.SETTINGThis was an add-on study of the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) which was also performed in a separate memory clinic-based sample.PARTICIPANTSA total of 102 study participants were included as healthy controls (HC; n=25), cognitively unimpaired first-degree relatives of AD patients (REL; n=7), individuals with subjective cognitive decline (SCD; n= 48) or patients with mild cognitive impairment (MCI; n=22).MEASUREMENTSWe analyzed results from the objects-in-rooms recall (ORR) test, the mnemonic discrimination for objects and scenes (MDT-OS) test and the complex scene recognition (CSR) test implemented on the neotiv digital platform to derive a Remote Digital Memory Composite. Participants used the neotiv mobile app to complete one unsupervised test session every two weeks on their own mobile device in an environment of their choice. We assessed the relationships of the Remote Digital Memory Composite acquired through the mobile app and in-clinic measures of the PACC5 conducted by trained neuropsychologists in the memory clinics participating in the DELCODE study.RESULTS102 participants provided technically complete data for at least one single session of each of the three test paradigms, of which 87 participants provided data from at least two test sessions of each task. The derived Remote Digital Memory Composite score was highly correlated with the PACC5 score across all participants (r=.75, pCONCLUSIONOur results indicate that unsupervised mobile cognitive assessments in a memory clinic setting using the implementation in the neotiv digital platform has high construct validity and results in a good discrimination between cognitively impaired and unimpaired individuals based on the PACC5 score. Thus, it is feasible to complement neuropsychological assessment of episodic memory with unsupervised, remote assessments on mobile devices. This contributes to recent efforts for implementing remotely performed episodic memory assessment for case-finding and monitoring in large research trials and clinical care.

Progrediente kognitive Einbusen sind das klinische Leitsymptom der Alzheimer-Erkrankung. Die genaue Erfassung kognitiver Defizite und die Beurteilung ihrer Progredienz bereiten jedoch in der Versorgung und Fruhintervention grose Probleme. Welche Probleme ergeben sich aus der aktuellen Praxis des kognitiven Assessments von Patienten mit dem Leitsymptom Gedachtnisprobleme fur die Versorgung und Fruhintervention und welche Moglichkeiten ergeben sich aus dem Einsatz mobiler Apps? Auswertung aktueller Versorgungsstrukturen, Diskussion von Grundlagenarbeiten und Expertenempfehlungen und aktueller Entwicklungen. Die aktuelle Praxis der „Paper-pencil“-basierten und zeitlich sowie ortlich an die Praxis- und Klinikumgebung gebundenen Diagnostik kognitiver Defizite beeintrachtigt die Durchfuhrbarkeit, Validitat und Reliabilitat des kognitiven Assessments und die Einschatzung der Progredienz kognitiver Defizite und limitiert so einen sinnvollen Einsatz fur weiterfuhrende diagnostische Masnahmen und therapeutische Entscheidungen. Aktuelle Entwicklungen mobiler Apps, hier am Beispiel der neotiv-App exemplarisch dargestellt, konnen helfen, diese Probleme zu uberwinden. Mobile App-basierte Technologien konnen helfen, die kognitive Diagnostik von Patienten mit dem Leitsymptom Gedachtnisprobleme zu verbessern. Sie konnen Uber- und Unterversorgung reduzieren und einen gezielten und sinnvollen Einsatz weiterfuhrender Diagnostik ermoglichen. Daruber hinaus konnen sie risikomodifizierende praventive Masnahmen strukturieren, helfen iatrogene Ursachen kognitiver Probleme zu erkennen und in dieser Hinsicht auch die Patientenkompetenz starken.

Although several studies have shown decreased cerebral blood flow (CBF) in Alzheimers disease (AD), the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, positron emission tomography, and biomarkers of cerebrospinal fluid, we investigated the associations between CBF and the key mechanisms in AD including amyloid-{beta} (A{beta}) and tau pathology, synaptic dysfunction and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in the temporo-occipito-parietal regions in the A{beta}-positive cognitively impaired compared to both the A{beta}-positive and A{beta}-negative cognitively unimpaired individuals. In participants along the AD spectrum (those with A{beta} pathology regardless of their cognitive status), CBF was inversely associated with tau and synaptic dysfunction, but not A{beta}, in similar cortical regions. Moreover, the disease progression modeling revealed that CBF disruption followed the abnormality of biomarkers of A{beta}, tau and brain atrophy. These findings indicate that tau tangles and synaptic degeneration are more closely connected with CBF changes rather than A{beta} pathology. This supports the notion that hypoperfusion is not an early event associated with the build-up of A{beta} during the preclinical phase of AD.

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), using18F-Flortaucipir for tau and11C-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 STATEMENTAbnormal 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.

There is an urgent need for inexpensive and minimally invasive blood biomarkers for Alzheimer disease (AD) that could be used to detect early disease changes.To assess how early in the course of AD plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of AD pathology.This cohort study included cognitively healthy control individuals (n = 225) and participants with subjective cognitive decline (n = 89) or mild cognitive impairment (n = 176) from the BioFINDER-2 study. Participants were enrolled at 2 different hospitals in Sweden from January 2017 to October 2019. All study participants underwent plasma P-tau217 assessments and tau- and amyloid-β (Aβ)-PET imaging. A subcohort of 111 participants had 2 or 3 tau-PET scans.Changes in plasma P-tau217 levels in preclinical and prodromal AD compared with changes in CSF P-tau217 and PET measures.Of 490 participants, 251 were women (51.2%) and the mean (SD) age was 65.9 (13.1) years. Plasma P-tau217 levels were increased in cognitively unimpaired participants with abnormal Aβ-PET but normal tau-PET in the entorhinal cortex (Aβ-PET+/ tau-PET- group vs Aβ-PET-/ tau-PET- group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] vs 0.7 pg/mL [IQR, 0.3-1.4 pg/mL]). Most cognitively unimpaired participants who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET (P-tau217+/tau-PET-: 36 [94.7%]; P-tau217-/tau-PET+: 2 [5.3%]). Event-based modeling of cross-sectional data predicted that in cognitively unimpaired participants and in those with mild cognitive impairment, both plasma and CSF P-tau217 would change before the tau-PET signal in the entorhinal cortex, followed by more widespread cortical tau-PET changes. When testing the association with global Aβ load in nonlinear spline models, both plasma and CSF P-tau217 were increased at lower Aβ-PET values compared with tau-PET measures. Among participants with normal baseline tau-PET, the rates of longitudinal increase in tau-PET in the entorhinal cortex were higher in those with abnormal plasma P-tau217 at baseline (median standardized uptake value ratio, 0.029 [IQR, -0.006 to 0.041] vs -0.001 [IQR, -0.021 to 0.020]; Mann-Whitney U, P = .02).In this cohort study, plasma P-tau217 levels were increased during the early preclinical stages of AD when insoluble tau aggregates were not yet detectable by tau-PET. Plasma P-tau217 may hold promise as a biomarker for early AD brain pathology.

Recent findings suggest that the effect of aging on recognition memory is modality-dependent, affecting memory for objects and scenes differently. However, the lifespan trajectory of memory decline in these domains remains unclear. A major challenge for assessing domain-specific trajectories is the need to utilize different types of stimuli for each domain (objects and scenes). We tested the large sample required to cover much of the adult lifespan using a large stimulus range via web-based assessments. 1554 participants (18–77 years) performed an online mnemonic discrimination task, tested on a pool of 2708 stimuli (Berron et al., 2018). Using corrected hit-rate (Pr) as a measure of performance, we show age-related decline in mnemonic discrimination in both domains, notably with a stronger decline in object memory, driven by a linear increase in the false recognition rate with advancing age. These data are the first to identify a linear age-related decline in mnemonic discrimination and a stronger, linear trajectory of decline in the object domain. Our data can inform basic and clinical memory research on the effects of aging on memory and help advancing the implementation of digital cognitive research tools.

Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images., In this commentary, we outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies. This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images.

ObjectiveEstimate the time-course of the spread of key pathological markers and the onset of cognitive dysfunction in Alzheimer’s disease.MethodsIn a cohort of 336 older adults, ranging in cognitive functioning, we estimated the time of initial changes of Aβ, tau, and decreases in cognition with respect to the time of Aβ-positivity.ResultsSmall effect sizes of change in CSF Aβ42 and regional Aβ PET were estimated to occur several decades before Aβ-positivity. Increases in CSF tau occurred 11-12 years before Aβ-positivity. Temporoparietal tau PET showed increases 4-5 years before Aβ-positivity. Subtle cognitive dysfunction was observed 7-9 years before Aβ-positivity.ConclusionsIncreases in tau and cognitive dysfunction occur years before the presence of significant Aβ. Explicit estimates of the time for these events provide a clearer picture of the time course of the amyloid cascade and identify potential windows for specific treatments.

For memory retrieval, pattern completion is a crucial process that restores memories from partial or degraded cues. Neurocognitive aging models suggest that the aged memory system is biased toward pattern completion, resulting in a behavioral preference for retrieval over encoding of memories. Here, we built on our previously developed behavioral recognition memory paradigm—the Memory Image Completion (MIC) task—a task to specifically target pattern completion. First, we used the original design with concurrent eye‐tracking in order to rule out perceptual confounds that could interact with recognition performance. Second, we developed parallel versions of the task to accommodate test settings in clinical environments or longitudinal studies. The results show that older adults have a deficit in pattern completion ability with a concurrent bias toward pattern completion. Importantly, eye‐tracking data during encoding could not account for age‐related performance differences. At retrieval, spatial viewing patterns for both age groups were more driven by stimulus identity than by response choice, but compared to young adults, older adults' fixation patterns overlapped more between stimuli that they (wrongly) thought had the same identity. This supports the observation that older adults choose responses perceived as similar to a learned stimulus, indicating a bias toward pattern completion. Additionally, two shorter versions of the task yielded comparable results, and no general learning effects were observed for repeated testing. Together, we present evidence that the MIC is a reliable behavioral task that targets pattern completion, that is easily and repeatedly applicable, and that is made freely available online.

Alzheimer’s disease researchers have been intrigued by the selective regional vulnerability of the brain to amyloid-β plaques and tau neurofibrillary tangles. Post-mortem studies indicate that in ageing and Alzheimer’s disease tau tangles deposit early in the transentorhinal cortex, a region located in the anterior-temporal lobe that is critical for object memory. In contrast, amyloid-β pathology seems to target a posterior-medial network that subserves spatial memory. In the current study, we tested whether anterior-temporal and posterior-medial brain regions are selectively vulnerable to tau and amyloid-β deposition in the progression from ageing to Alzheimer’s disease and whether this is reflected in domain-specific behavioural deficits and neural dysfunction. 11C-PiB PET and 18F-flortaucipir uptake was quantified in a sample of 131 cognitively normal adults (age: 20–93 years; 47 amyloid-β-positive) and 20 amyloid-β-positive patients with mild cognitive impairment or Alzheimer’s disease dementia (65–95 years). Tau burden was relatively higher in anterior-temporal regions in normal ageing and this difference was further pronounced in the presence of amyloid-β and cognitive impairment, indicating exacerbation of ageing-related processes in Alzheimer’s disease. In contrast, amyloid-β deposition dominated in posterior-medial regions. A subsample of 50 cognitively normal older (26 amyloid-β-positive) and 25 young adults performed an object and scene memory task while functional MRI data were acquired. Group comparisons showed that tau-positive (n = 18) compared to tau-negative (n = 32) older adults showed lower mnemonic discrimination of object relative to scene images [t(48) = −3.2, P = 0.002]. In a multiple regression model including regional measures of both pathologies, higher anterior-temporal flortaucipir (tau) was related to relatively worse object performance (P = 0.010, r = −0.376), whereas higher posterior-medial PiB (amyloid-β) was related to worse scene performance (P = 0.037, r = 0.309). The functional MRI data revealed that tau burden (but not amyloid-β) was associated with increased task activation in both systems and a loss of functional specificity, or dedifferentiation, in posterior-medial regions. The loss of functional specificity was related to worse memory. Our study shows a regional dissociation of Alzheimer’s disease pathologies to distinct memory networks. While our data are cross-sectional, they indicate that with ageing, tau deposits mainly in the anterior-temporal system, which results in deficits in mnemonic object discrimination. As Alzheimer’s disease develops, amyloid-β deposits preferentially in posterior-medial regions additionally compromising scene discrimination and anterior-temporal tau deposition worsens further. Finally, our findings propose that the progression of tau pathology is linked to aberrant activation and dedifferentiation of specialized memory networks that is detrimental to memory function.

Retention of 18F-Flortaucipir is reportedly increased in the semantic variant of primary progressive aphasia (svPPA), which is dominated by TDP-43 pathology. However, it is unclear if 18F-Flortaucipir is also increased in other TDP-43 diseases, such as bvFTD caused by a C9orf72 gene mutation. We therefore recruited six C9orf72 expansion carriers, six svPPA patients, and 54 healthy controls. All underwent 18F-Flortaucipir PET and MRI scanning. Data from 39 Alzheimer’s Disease patients were used for comparison. PET tracer retention was assessed both at the region-of-interest (ROI) and at the voxel-level. Further, autoradiography using 3H-Flortaucipir was performed. SvPPA patients exhibited higher 18F-Flortaucipir retention in the lateral temporal cortex bilaterally according to ROI- and voxel-based analyses. In C9orf72 patients, 18F-Flortaucipir binding was slightly increased in the inferior frontal lobes in the ROI based analysis, but these results were not replicated in the voxel-based analysis. Autoradiography did not show specific binding in svPPA cases or in C9orf72-mutation carriers. In conclusion, temporal lobe 18F-Flortaucipir retention was observed in some cases of svPPA, but the uptake was of a lower magnitude compared to AD dementia. C9orf72-mutation carriers exhibited none or limited 18F-Flortaucipir retention, indicating that 18F-Flortaucipir binding in TDP-43 proteinopathies is not a general TDP-43 related phenomenon.

The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies. © 2016 Wiley Periodicals, Inc.

Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here, we show that a muscle secretory factor, cathepsin B (CTSB) protein, is important for the cognitive and neurogenic benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a mechanism dependent on the multifunctional protein P11. In vivo, in CTSB knockout (KO) mice, running did not enhance adult hippocampal neurogenesis and spatial memory function. Interestingly, in Rhesus monkeys and humans, treadmill exercise elevated CTSB in plasma. In humans, changes in CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition.

The hippocampus plays a central role in the approach–avoidance conflict that is central to the genesis of anxiety. However, its exact functional contribution has yet to be identified. We designed a novel gambling task that generated approach–avoidance conflict while controlling for spatial processing. We fit subjects’ behavior using a model that quantified the subjective values of choice options, and recorded neural signals using functional magnetic resonance imaging (fMRI). Distinct functional signals were observed in anterior hippocampus, with inferior hippocampus selectively recruited when subjects rejected a gamble, to a degree that covaried with individual differences in anxiety. The superior anterior hippocampus, in contrast, uniquely demonstrated value signals that were potentiated in the context of approach–avoidance conflict. These results implicate the anterior hippocampus in behavioral avoidance and choice monitoring, in a manner relevant to understanding its role in anxiety. Our findings highlight interactions between subregions of the hippocampus as an important focus for future study.

The entorhinal cortex (EC) is the primary site of interactions between the neocortex and hippocampus. Studies in rodents and nonhuman primates suggest that EC can be divided into subregions that connect differentially with perirhinal cortex (PRC) vs parahippocampal cortex (PHC) and with hippocampal subfields along the proximo-distal axis. Here, we used high-resolution functional magnetic resonance imaging at 7 Tesla to identify functional subdivisions of the human EC. In two independent datasets, PRC showed preferential intrinsic functional connectivity with anterior-lateral EC and PHC with posterior-medial EC. These EC subregions, in turn, exhibited differential connectivity with proximal and distal subiculum. In contrast, connectivity of PRC and PHC with subiculum followed not only a proximal-distal but also an anterior-posterior gradient. Our data provide the first evidence that the human EC can be divided into functional subdivisions whose functional connectivity closely parallels the known anatomical connectivity patterns of the rodent and nonhuman primate EC. DOI: http://dx.doi.org/10.7554/eLife.06426.001, eLife digest In the early 1950s, an American named Henry Molaison underwent an experimental type of brain surgery to treat his severe epilepsy. The surgeon removed a region of the brain known as the temporal lobe from both sides of his brain. After the surgery, Molaison's epilepsy was greatly improved, but he was also left with a profound amnesia, unable to form new memories of recent events. Subsequent experiments, including many with Molaison himself as a subject, have attempted to identify the roles of the various structures within the temporal lobes. The hippocampus—which is involved in memory and spatial navigation—has received the most attention, but in recent years a region called the entorhinal cortex has also come to the fore. Known as the gateway to the hippocampus, the entorhinal cortex relays sensory information from the outer cortex of the brain to the hippocampus. In rats and mice the entorhinal cortex can be divided into two subregions that have distinct connections to other parts of the temporal lobe. The ‘medial entorhinal cortex’ is the subregion nearest the centre of the brain, and it predominantly connects to parahippocampal cortex, which is involved in processing visual scenes. The other subregion, the ‘lateral entorhinal cortex’, is to the left or right of the center and has particularly strong connections to the perirhinal cortex, which is involved in the memory of objects. The two subregions are also connected to different parts of the hippocampus. For many years researchers had assumed that the connectivity of the human entorhinal cortex was quite similar to that observed in rats and mice. However, it was not possible to check this as the entorhinal cortex measures less than about 1 cm across, which placed it beyond the reach of most commonly available brain-imaging techniques. Now, two independent groups of researchers have used ultra high-resolution functional magnetic resonance imaging (fMRI) to reveal a more complex structure in humans. The fMRI data reveal that the entorhinal cortex is divided into an anterior-lateral (to the front and at the side) subregion and a posterior-medial (to the back and at the centre) subregion in humans. One of the groups—Maass, Berron et al.—used the imaging data to show that the anterior-lateral and posterior-medial subregions of the entorhinal cortex form distinct patterns of connections with the perirhinal cortex and the parahippocampal cortex, as well as with different parts of the hippocampus. The other group—Navarro Schröder, Haak et al.—studied functional connections across the whole neocortex to come to the same conclusions. The discovery of these networks in the temporal lobe in humans will help to bridge the gap between studies of memory in rodents and in humans. Given that the lateral entorhinal cortex is one of the first regions to be affected in Alzheimer's disease, identifying the specific properties and roles of these networks could also provide insights into disease mechanisms. DOI: http://dx.doi.org/10.7554/eLife.06426.002

Several studies demonstrated that visual filtering mechanisms might underlie both conflict resolution of the Flanker conflict and the control of the Garner effect. However, it remains unclear whether the mechanisms involved in the processing of both effects depend on similar filter mechanisms, such that especially the Garner effect is able to modulate filtering needs in the Flanker conflict. In the present experiment twenty-four subjects participated in a combined Garner and Flanker task during two runs of functional magnetic resonance imaging (fMRI) recordings. Behavioral data showed a significant Flanker but no Garner effect. A run-wise analysis, however, revealed a Flanker effect in the Garner filtering condition in the first experimental run, while we found a Flanker effect in the Garner baseline condition in the second experimental run. The fMRI data revealed a fronto-parietal network involved in the processing of both types of effects. Flanker interference was associated with activity in the inferior frontal gyrus, the anterior cingulate cortex, the precuneus as well as the inferior (IPL) and superior parietal lobule (SPL). Garner interference was associated with activation in middle frontal and middle temporal gyrus, the lingual gyrus as well as the IPL and SPL. Interaction analyses between the Garner and the Flanker effect additionally revealed differences between the two experimental runs. In the first experimental run, activity specifically related to the interaction of effects was found in frontal and parietal regions, while in the second run we found activity in the hippocampus, the parahippocampal cortex and the basal ganglia. This shift in activity for the interaction effects might be associated with a task-related learning process to control filtering demands. Especially perceptual learning mechanisms might play a crucial role in the present Flanker and Garner task design and, therefore, increased performance in the second experimental run could be the reason for the lack of behavioral Garner interference on the level of the whole experiment.