Bernard Hanseeuw

Defining face perception areas in the human brain : a large-scale factorial fMRI face localizer analysis

A number of human brain areas showing a larger response to faces than to objects from different categories, or to scrambled faces, have been identified in neuroimaging studies. Depending on the statistical criteria used, the set of areas can be overextended or minimized, both at the local (size of areas) and global (number of areas) levels. Here we analyzed a whole-brain factorial functional localizer obtained in a large sample of right-handed participants (40). Faces (F), objects (O; cars) and their phase-scrambled counterparts (SF, SO) were presented in a block design during a one-back task that was well matched for difficulty across conditions. A conjunction contrast at the group level {(F-SF) and (F-O)} identified six clusters: in the pulvinar, inferior occipital gyrus (so-called OFA), middle fusiform gyrus (so-called FFA), posterior superior temporal sulcus, amygdala, and anterior infero-temporal cortex, which were all strongly right lateralized. While the FFA showed the largest difference between faces and cars, it also showed the least face-selective response, responding more to cars than scrambled cars. Moreover, the FFAs larger response to scrambled faces than scrambled cars suggests that its face-sensitivity is partly due to low-level visual cues. In contrast, the pattern of activation in the OFA points to a higher degree of face-selectivity. A BOLD latency mapping analysis suggests that face-sensitivity emerges first in the right FFA, as compared to all other areas. Individual brain analyses support these observations, but also highlight the large amount of interindividual variability in terms of number, height, extent and localization of the areas responding preferentially to faces in the human ventral occipito-temporal cortex. This observation emphasizes the need to rely on different statistical thresholds across the whole brain and across individuals to define these areas, but also raises some concerns regarding any objective labeling of these areas to make them correspond across individual brains. This large-scale analysis helps understanding the set of face-sensitive areas in the human brain, and encourages in-depth single participant analyses in which the whole set of areas is considered in each individual brain.

Mild Cognitive Impairment: Differential Atrophy in the Hippocampal Subfields

BACKGROUND AND PURPOSE: Hippocampus volumetry is a useful surrogate marker for the diagnosis of Alzheimer disease, but it seems insufficiently sensitive for the aMCI stage. We postulated that some hippocampus subfields are specifically atrophic in aMCI and that measuring hippocampus subfield volumes will improve sensitivity of MR imaging to detect aMCI. MATERIALS AND METHODS: We evaluated episodic memory and hippocampus subfield volume in 15 patients with aMCI and 15 matched controls. After segmentation of the whole hippocampus from clinical MR imaging, we applied a new computational method allowing fully automated segmentation of the hippocampus subfields. This method used a Bayesian modeling approach to infer segmentations from the imaging data. RESULTS: In comparison with controls, subiculum and CA2–3 were significantly atrophic in patients with aMCI, whereas total hippocampus volume and other subfields were not. Total hippocampus volume in controls was age-related, whereas episodic memory was the main explanatory variable for both the total hippocampus volume and the subfields that were atrophic in patients with aMCI. Segmenting subfields increases sensitivity to diagnose aMCI from 40% to 73%. CONCLUSIONS: Measuring CA2–3 and subiculum volumes allows a better detection of aMCI.

Heterogeneity in Suspected Non-Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals.

Importance A substantial proportion of clinically normal (CN) older individuals are classified as having suspected non-Alzheimer disease pathophysiology (SNAP), defined as biomarker negative for β-amyloid (Aβ-) but positive for neurodegeneration (ND+). The etiology of SNAP in this population remains unclear. Objective To determine whether CN individuals with SNAP show evidence of early Alzheimer disease (AD) processes (ie, elevated tau levels and/or increased risk for cognitive decline). Design, Setting, and Participants This longitudinal observational study performed in an academic medical center included 247 CN participants from the Harvard Aging Brain Study. Participants were classified into preclinical AD stages using measures of Aβ (Pittsburgh Compound B [PIB]-labeled positron emission tomography) and ND (hippocampal volume or cortical glucose metabolism from AD-vulnerable regions). Classifications included stages 0 (Aβ-/ND-), 1 (Aβ+/ND-), and 2 (Aβ+/ND+) and SNAP (Aβ-/ND+). Continuous levels of PiB and ND, tau levels in the medial and inferior temporal lobes, and longitudinal cognition were examined. Data collection began in 2010 and is ongoing. Data were analyzed from 2015 to 2016. Main Outcomes and Measures Evidence of amyloid-independent tau deposition and/or cognitive decline. Results Of the 247 participants (142 women [57.5%]; 105 men [42.5%]; mean age, 74 [range, 63-90] years), 64 (25.9%) were classified as having SNAP. Compared with the stage 0 group, the SNAP group was not more likely to have subthreshold PiB values (higher values within the Aβ- range), suggesting that misclassification due to the PiB cutoff was not a prominent contributor to this group (mean [SD] distribution volume ratio, 1.08 [0.05] for the SNAP group; 1.09 [0.05] for the stage 1 group). Tau levels in the medial and inferior temporal lobes were indistinguishable between the SNAP and stage 0 groups (entorhinal cortex, β = -0.005 [SE, 0.036]; parahippocampal gyrus, β = -0.001 [SE, 0.027]; and inferior temporal lobe, β = -0.004 [SE, 0.027]; P ≥ .88) and were lower in the SNAP group compared with the stage 2 group (entorhinal cortex, β = -0.125 [SE, 0.041]; parahippocampal gyrus, β = -0.074 [SE, 0.030]; and inferior temporal lobe, β = -0.083 [SE, 0.031]; P ≤ .02). The stage 2 group demonstrated greater cognitive decline compared with all other groups (stage 0, β = -0.239 [SE, 0.042]; stage 1, β = -0.242 [SE, 0.051]; and SNAP, β = -0.157 [SE, 0.044]; P ≤ .001), whereas the SNAP group showed a diminished practice effect over time compared with the stage 0 group (β = -0.082 [SE, 0.037]; P = .03). Conclusions and Relevance In this study, clinically normal adults with SNAP did not exhibit evidence of elevated tau levels, which suggests that this biomarker construct does not represent amyloid-independent tauopathy. At the group level, individuals with SNAP did not show cognitive decline but did show a diminished practice effect. SNAP is likely heterogeneous, with a subset of this group at elevated risk for short-term decline. Future refinement of biomarkers will be necessary to subclassify this group and determine the biological correlates of ND markers among Aβ- CN individuals.

Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals

Alzheimers disease (AD) is characterized by two hallmark molecular pathologies: amyloid aβ1–42 and Tau neurofibrillary tangles. To date, studies of functional connectivity MRI (fcMRI) in individuals with preclinical AD have relied on associations with in vivo measures of amyloid pathology. With the recent advent of in vivo Tau-PET tracers it is now possible to extend investigations on fcMRI in a sample of cognitively normal elderly humans to regional measures of Tau. We modeled fcMRI measures across four major cortical association networks [default-mode network (DMN), salience network (SAL), dorsal attention network, and frontoparietal control network] as a function of global cortical amyloid [Pittsburgh Compound B (PiB)-PET] and regional Tau (AV1451-PET) in entorhinal, inferior temporal (IT), and inferior parietal cortex. Results showed that the interaction term between PiB and IT AV1451 was significantly associated with connectivity in the DMN and salience. The interaction revealed that amyloid-positive (aβ+) individuals show increased connectivity in the DMN and salience when neocortical Tau levels are low, whereas aβ+ individuals demonstrate decreased connectivity in these networks as a function of elevated Tau-PET signal. This pattern suggests a hyperconnectivity phase followed by a hypoconnectivity phase in the course of preclinical AD. SIGNIFICANCE STATEMENT This article offers a first look at the relationship between Tau-PET imaging with F18-AV1451 and functional connectivity MRI (fcMRI) in the context of amyloid-PET imaging. The results suggest a nonlinear relationship between fcMRI and both Tau-PET and amyloid-PET imaging. The pattern supports recent conjecture that the AD fcMRI trajectory is characterized by periods of both hyperconnectivity and hypoconnectivity. Furthermore, this nonlinear pattern can account for the sometimes conflicting reports of associations between amyloid and fcMRI in individuals with preclinical Alzheimers disease.

Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline: Tau, Amyloid, FDG, and Memory in Normal Aging

The aim of this article was to evaluate in normal older adults and preclinical Alzheimers disease (AD) the impact of amyloid and regional tauopathy on cerebral glucose metabolism and subsequent memory decline.

Associative encoding deficits in amnestic mild cognitive impairment : a volumetric and functional MRI study.

BACKGROUND Previous functional MRI studies have shown increased hippocampus activation in response to item encoding in amnestic mild cognitive impairment (aMCI). Recent behavioral studies suggested that associative memory could be more impaired than item memory in aMCI. So far, associative encoding has not been evaluated separately from item encoding in functional MRI studies. METHODS We conducted a volumetric and functional MRI study investigating associative encoding in 16 aMCI and 16 elderly controls while controlling for item encoding. RESULTS We confirmed the presence of associative memory impairment in aMCI even after controlling for item memory differences between groups. Associative memory but not item memory correlated with hippocampus volume in aMCI. Such a correlation was not observed in elderly controls. The left anterior hippocampus activation in response to successful associative encoding was decreased in aMCI, even after correction for hippocampus atrophy. CONCLUSION Associative memory impairment in aMCI appears to be related to hippocampus atrophy and left anterior hippocampus hypoactivation.

FDG metabolism associated with tau‐amyloid interaction predicts memory decline

The aim of this article was to evaluate in normal older adults and preclinical Alzheimers disease (AD) the impact of amyloid and regional tauopathy on cerebral glucose metabolism and subsequent memory decline.

Classification of Non-Demented Patients Attending a Memory Clinic using the New Diagnostic Criteria for Alzheimer's Disease with Disease-Related Biomarkers

BACKGROUND New diagnostic criteria for predemential Alzheimers disease (AD) advocate the use of biomarkers. However, the benefit of using biomarkers has not been clearly demonstrated in clinical practice. OBJECTIVE To investigate whether a combination of biomarkers may be helpful in classifying a population of non-demented patients attending a Memory Clinic. METHODS Sixty non-demented patients were compared with 31 healthy elderly subjects. All subjects underwent a neuropsychological examination, brain 3T magnetic resonance imaging, [F18]-fluorodeoxyglucose and [F18]-flutemetamol positron emission tomography. According to their performance on memory, language, executive, and visuo-spatial domains, the patients were classified as mild cognitive impairment (amnestic, non-amnestic, single, or multiple domain) or subjective cognitive impairment. Patients were then classified according to the National Institute on Aging-Alzheimers Association (NIA-AA) criteria, using the normalized mean hippocampal volume (Freesurfer), [F18]-FDG PALZAD, and [F18]-flutemetamol standard uptake value ratio (SUVr) (cut-off at the 10th percentile of controls). The standard of truth was the clinical status at study entry (patient versus control). RESULTS The sensitivity/specificity of the clinical classification was 65/84%. The NIA-AA criteria were applicable in 85% of patients and 87% of controls. For biomarkers the best sensitivity (72%) at a fixed specificity of 84% was achieved by a combination of the three biomarkers. The clinical diagnosis was reconsidered in more than one third of the patients (42%) as a result of including the biomarker results. CONCLUSIONS Application of the new NIA-AA AD diagnostic criteria based on biomarkers in an unselected sample of non-demented patients attending a Memory Clinic was useful in allowing for a better classification of the subjects.

Early and late change on the preclinical Alzheimer's cognitive composite in clinically normal older individuals with elevated amyloid-β

Sensitive detection of cognitive decline over the course of preclinical Alzheimers disease is critical as the field moves toward secondary prevention trials.

Hierarchical Organization of Tau and Amyloid Deposits in the Cerebral Cortex

Importance Abnormal accumulation of tau and amyloid-&bgr; (A&bgr;) proteins in the human brain are 2 pathologic hallmarks of Alzheimer disease (AD). Because pathologic processes begin decades before the onset of the clinical manifestations, the study of the cortical distribution of early-stage pathologic alterations is critical in understanding the underpinnings of the disease. Objectives To identify the in vivo brain spatial distributions of tau and A&bgr; deposits in a sample of cognitively normal participants in the Harvard Aging Brain Study, determine spatial patterns of pathologic alterations, and provide means for improved individual in vivo staging. Design, Setting, and Participants Eighty-eight individuals from the general community underwent flortaucipir 18 T807 (18F-T807) and carbon 11–labeled Pittsburgh Compound B (11C-PiB) positron emission tomographic (PET) imaging. A voxel-level hierarchical clustering approach was used to obtain the main clustering partitions corresponding to the cortical distribution maps of 18F-T807 and 11C-PiB. Hierarchical relationships between areas of distinctive pathologic deposits were then studied. Using cerebellar gray reference, 18F-T807 data were expressed as standardized uptake value ratio, and 11C-PiB were given as distribution volume ratio. Main Outcomes and Measures Main in vivo and hierarchically organized tau and A&bgr; deposits in the elderly brain. Results Of the 88 study participants, 39 (44%) were men, with a mean (SD) age of 76.2 (6.2) years. The tau and A&bgr; maps both displayed optimal cortical partitions at 4 clusters. The tau deposits were grouped in the temporal lobe, distributed in heteromodal areas, medial and visual regions, and primary somatomotor cortex; the A&bgr; deposits were clustered in the heteromodal areas and rather patchy in distributed regions involving the primary cortices, medial structures, and temporal areas. Moreover, tau deposits in the temporal lobe and distributed heteromodal areas were tightly nested. Conclusions and Relevance Tau and A&bgr; deposits in the elderly brain generally display well-defined hierarchical cortical relationships as well as overlaps between the principal clusters of both pathologic alterations in the heteromodal association regions. These findings represent systematic, large-scale mechanisms of early AD pathology.