Evidence against altered excitatory/inhibitory balance in the posteromedial cortex of young adult APOE E4 carriers: A resting state 1H-MRS study.

A strategy to gain insight into early changes that may predispose people to Alzheimer's disease (AD) is to study the brains of younger cognitively healthy people that are at increased genetic risk of AD. The Apolipoprotein (APOE) E4 allele is the strongest genetic risk factor for AD, and several neuroimaging studies comparing APOE E4 carriers with non-carriers at age ∼20-30 years have detected hyperactivity (or reduced deactivation) in posteromedial cortex (PMC), a key hub of the default network (DN), which has a high susceptibility to early amyloid deposition in AD. Transgenic mouse models suggest such early network activity alterations may result from altered excitatory/inhibitory (E/I) balance, but this is yet to be examined in humans. Here we test the hypothesis that PMC fMRI hyperactivity could be underpinned by altered levels of excitatory (glutamate) and/or inhibitory (GABA) neurotransmitters in this brain region. Forty-seven participants (20 APOE E4 carriers and 27 non-carriers) aged 18-25 years underwent resting-state proton magnetic resonance spectroscopy (1H-MRS), a non-invasive neuroimaging technique to measure glutamate and GABA in vivo. Metabolites were measured in a PMC voxel of interest and in a comparison voxel in the occipital cortex (OCC). There was no difference in either glutamate or GABA between the E4 carriers and non-carriers in either MRS voxel, or in the ratio of glutamate to GABA, a measure of E/I balance. Default Bayesian t-tests revealed evidence in support of this null finding. Our findings suggest that PMC hyperactivity in APOE E4 carriers is unlikely to be associated with, or possibly may precede, alterations in local resting-state PMC neurotransmitters, thus informing our understanding of the spatio-temporal sequence of early network alterations underlying APOE E4 related AD risk.

Evidencing a place for the hippocampus within the core scene processing network.

Functional neuroimaging studies have identified several "core" brain regions that are preferentially activated by scene stimuli, namely posterior parahippocampal gyrus (PHG), retrosplenial cortex (RSC), and transverse occipital sulcus (TOS). The hippocampus (HC), too, is thought to play a key role in scene processing, although no study has yet investigated scene-sensitivity in the HC relative to these other "core" regions. Here, we characterised the frequency and consistency of individual scene-preferential responses within these regions by analysing a large dataset (n = 51) in which participants performed a one-back working memory task for scenes, objects, and scrambled objects. An unbiased approach was adopted by applying independently-defined anatomical ROIs to individual-level functional data across different voxel-wise thresholds and spatial filters. It was found that the majority of subjects had preferential scene clusters in PHG (max = 100% of participants), RSC (max = 76%), and TOS (max = 94%). A comparable number of individuals also possessed significant scene-related clusters within their individually defined HC ROIs (max = 88%), evidencing a HC contribution to scene processing. While probabilistic overlap maps of individual clusters showed that overlap "peaks" were close to those identified in group-level analyses (particularly for TOS and HC), inter-individual consistency varied across regions and statistical thresholds. The inter-regional and inter-individual variability revealed by these analyses has implications for how scene-sensitive cortex is localised and interrogated in functional neuroimaging studies, particularly in medial temporal lobe regions, such as the HC. Hum Brain Mapp 37:3779-3794, 2016. © 2016 Wiley Periodicals, Inc.

Temporal lobe contribution to perceptual function: A tale of three patient groups.

There has been growing recognition of the contribution of medial and anterior temporal lobe structures to non-mnemonic functions, such as perception. To evaluate the nature of this contribution, we contrast the perceptual performance of three patient groups, all of whom have a perturbation of these temporal lobe structures. Specifically, we compare the profile of patients with focal hippocampal (HC) lesions, those with more extensive lesions to the medial temporal lobe (MTL) that include HC and perirhinal cortex (PrC), and those with congenital prosopagnosia (CP), whose deficit has been attributed to the disconnection of the anterior temporal lobe from more posterior structures. All participants completed a range of'oddity' tasks in which, on each trial, they determined which of four visual stimuli in a display was the'odd-one-out'. There were five stimulus categories including faces, scenes, objects (high and low ambiguity) and squares of different sizes. Comparisons were conducted separately for the HC, MTL and CP groups against their matched control groups and then the group data were compared to each other directly. The group profiles were easily differentiable. Whereas the HC group stood out for its difficulty in discriminating scenes and the CP group stood out for its disproportionate difficulty in discriminating faces with milder effects for scenes and high ambiguity objects, the MTL group evinced a more general discrimination deficit for faces, scenes and high ambiguity objects. The group differences highlight distinct profiles for each of the three groups and distinguish the signature perceptual impairments following more extended temporal lobe alterations. In the recent reconsideration of the role of the hippocampus and neocortex, Moscovitch and colleagues (Moscovitch et al., 2016) note that the medial temporal lobe structures play a role in non-mnemonic functions, such as perception, problem solving, decision-making and language. Here, we address this exact issue, specifically with respect to perception, and we dedicate this paper to Morris Moscovitch in recognition of his profound contribution to science, to his students and to his colleagues.

APOE-ε4 selectively modulates posteromedial cortex activity during scene perception and short-term memory in young healthy adults.

Apolipoprotein E (APOE) ε4 is a major genetic risk factor for Alzheimer's disease (AD), yet the mechanisms by which APOE-ε4 influences early-life brain function, and hence, in turn, risk for later-life AD, are poorly understood. Here, we report a novel, and selective, pattern of functional brain activity alteration in healthy young adult human APOE-ε4 carriers. Our findings suggest that APOE-ε4 may influence vulnerability to poorer later life cognitive health via its effect on posteromedial cortex (PMC), a hub region within a brain network involved in spatial processing, and necessary for episodic memory. In two neuroimaging tasks, APOE-ε4 carriers showed an inability to effectively modulate PMC during scene, but not face and object, working memory and perception. This striking pattern overlaps both functionally and topographically, with the earliest cognitive deficits seen in clinical AD, as well as reported alterations in the default network in amyloid-positive individuals at increased risk of AD.

Extrastriate cortex and medial temporal lobe regions respond differentially to visual feature overlap within preferred stimulus category.

It has been proposed that domain-specific regions in extrastriate cortex, parahippocampal cortex and the medial temporal lobe (MTL, particularly the hippocampus, HC, and perirhinal cortex, PrC) may respond differently to the degree of feature complexity present in sets of visual stimuli, with the latter two regions tuned to represent the differences among stimuli with a high degree of visual overlap or featural ambiguity (Graham, Barense, & Lee, 2010; Cowell, Bussey, & Saksida, 2010a). To test this prediction, healthy participants viewed blocks containing visually similar or visually different exemplars from four stimulus categories (scenes, faces, inanimate objects and animate objects). Independent functional regions of interest were identified in extrastriate and MTL regions that were preferentially responsive to one or more of these visual categories, and the main experimental data interrogated for any evidence of an interaction between visual category and degree of feature overlap. In PrC and posterior HC (PostHC) viewing sets of stimuli with a large number of overlapping features resulted in greater activity than blocks containing items that were more visually distinct. The opposite pattern was found in fusiform face area (FFA), parahippocampal place area (PPA) and lateral occipital complex (LOC). The increased response in the HC and PrC to high visual similarity was seen only for visual categories that effectively activate these regions (PrC-faces and objects; PostHC-scenes). This study confirms that regions throughout the visual ventral stream, parahippocampal cortex and MTL are engaged differentially by visual complexity, consistent with recent lesion experiments in which MTL damage affects discrimination and learning of, as well as recognition memory for, exemplars with a high degree of visual feature overlap.

Design of a variable temperature scanning force microscope.

We have developed the variable temperature scanning force microscope capable of performing both magnetic resonance force microscopy (MRFM) and magnetic force microscopy (MFM) measurements in the temperature range between 5 and 300 K. Modular design, large scanning area, and interferometric detection of the cantilever deflection make it a sensitive, easy to operate, and reliable instrument suitable for studies of the dynamic and static magnetization in various systems. We have verified the performance of the microscope by imaging vortices in a Nb thin film in the MFM mode of operation. MRFM spectra in a diphenyl-picryl-hydrazyl film were recorded to evaluate the MRFM mode of operation.

Are judgments of semantic relatedness systematically impaired in Alzheimer's disease?

We employed a triadic comparison task in patients with Alzheimer's disease (AD) and healthy controls to contrast (a) multidimensional scaling (MDS) and accuracy-based assessments of semantic memory, and (b) degraded-store versus degraded-access accounts of semantic impairment in Alzheimer's disease (AD). Similar to other studies using triadic comparison tasks, participants were asked to indicate which two out of three words (animal names) were most similar in meaning. Novel to this investigation, we contrasted performance on two semantic dimensions of strong and equal saliency to controls, but varying in their specificity (land/water versus bird/non-bird). Degraded-store accounts predict that the more specific bird/non-bird dimension should be more consistently impaired in AD, whereas degraded-access accounts predict that both dimensions, because they are equally salient, should be equivalently impaired in the disorder. The MDS results suggested that both patient and control group responses were not discriminable from random responding, consistent with previous studies. By contrast an accuracy-based analysis on the same data showed that controls showed good knowledge of both salient dimensions, and were evenly split in their individual preference for one dimension over another. In contrast, patients showed higher accuracy and sensitivity to the broader land/water dimension than to the more specific bird/non-bird dimension, consistent with a storage-based account of the semantic impairment in AD. Our results further suggest that MDS methods can fail to reveal important and systematic behaviour in semantic tasks, in both patient and control groups.

Transient epileptic amnesia: regional brain atrophy and its relationship to memory deficits.

Transient epileptic amnesia (TEA) is a recently recognised form of epilepsy of which the principle manifestation is recurrent, transient episodes of isolated memory loss. In addition to the amnesic episodes, many patients describe significant interictal memory difficulties. Performance on standard neuropsychological tests is often normal. However, two unusual forms of memory deficit have recently been demonstrated in TEA: (i) accelerated long-term forgetting (ALF): the excessively rapid loss of newly acquired memories over a period of days or weeks and (ii) remote autobiographical memory loss: a loss of memories for salient, personally experienced events of the past few decades. The neuroanatomical bases of TEA and its associated memory deficits are unknown. In this study, we first assessed the relationship between subjective and objective memory performance in 41 patients with TEA. We then analysed MRI data from these patients and 20 matched healthy controls, using manual volumetry and voxel-based morphometry (VBM) to correlate regional brain volumes with clinical and neuropsychological data. Subjective memory estimates were unrelated to performance on standard neuropsychological tests but were partially predicted by mood, ALF and remote autobiographical memory. Manual volumetry identified subtle hippocampal volume loss in the patient group. Both manual volumetry and VBM revealed correlations between medial temporal lobe atrophy and standard anterograde memory scores, but no relation between atrophy and ALF or remote autobiographical memory. These results add weight to the hypothesis that TEA is a syndrome of mesial temporal lobe epilepsy. Furthermore, they suggest that although standard anterograde memory test performance is related to the degree of mesial temporal lobe damage, this is not true for ALF and autobiographical amnesia. It is possible that these unusual memory deficits have a more diffuse physiological basis rather than being a consequence of discrete structural damage.

Repetition priming and hyperpriming in semantic dementia.

Evidence from neurologically normal subjects suggests that repetition priming (RP) is independent of semantic processing. Therefore, we may expect patients with a selective deficit to conceptual knowledge to exhibit RP for words regardless of the integrity of their semantic representations. We tested six patients with semantic dementia (SD) on a lexical decision task that incorporated four different lags between first (baseline) and second (primed) presentation of repeated words. The patients exhibited significant RP that was greater for words that were categorised as semantically 'degraded' than for words categorised as 'known.' This RP advantage for semantically degraded words declined as lag increased. The patients also demonstrated hyperpriming, and a significant correlation was identified between baseline response time and RP in SD but not in controls. These findings indicate that level of semantic knowledge about a word influences both baseline lexical decision performance and RP of that word. The observed hyperpriming can be parsimoniously explained by a cognitive slowing account.

A horse of a different colour: do patients with semantic dementia recognise different versions of the same object as the same?

Ten patients with semantic dementia resulting from bilateral anterior temporal lobe atrophy, and 10 matched controls, were tested on an object recognition task in which they were invited to choose (from a four-item array) the picture representing "the same thing" as an object picture that they had just inspected and attempted to name. The target in the response array was never physically identical to the studied picture but differed from it - in the various conditions - in size, angle of view, colour or exemplar (e.g. a different breed of dog). In one test block for each patient, the response array was presented immediately after the studied picture was removed; in another block, a 2 min filled delay was inserted between study and test. The patients performed relatively well when the studied object and target response differed only in the size of the picture on the page, but were significantly impaired as a group in the other three type-of-change conditions, even with no delay between study and test. The five patients whose structural brain imaging revealed major right-temporal atrophy were more impaired overall, and also more affected by the 2 min delay, than the five patients with an asymmetric pattern characterised by predominant left-sided atrophy. These results are interpreted in terms of a hypothesis that successful classification of an object token as an object type is not a pre-semantic ability but rather results from interaction of perceptual and conceptual processing.

Autobiographical amnesia and accelerated forgetting in transient epileptic amnesia.

BACKGROUND: Recurrent brief isolated episodes of amnesia associated with epileptiform discharges on EEG recordings have been interpreted as a distinct entity termed transient epileptic amnesia (TEA). Patients with TEA often complain of autobiographical amnesia for recent and remote events, but show normal anterograde memory. OBJECTIVE: To investigate (a) accelerated long term forgetting and (b) autobiographical memory in a group of patients with TEA. METHODS: Seven patients with TEA and seven age matched controls were evaluated on a range of anterograde memory tasks in two sessions separated by 6 weeks and by the Galton-Crovitz test of cued autobiographical memory. RESULTS: Patients with TEA showed abnormal long term forgetting of verbal material, with virtually no recall after 6 weeks. In addition, there was impaired recall of autobiographical memories from the time periods 1985-89 and 1990-94 but not from 1995-1999. CONCLUSIONS: TEA is associated with accelerated loss of new information and impaired remote autobiographical memory. There are a number of possible explanations including ongoing subclinical ictal activity, medial temporal lobe damage as a result of seizure, or subtle ischaemic pathology. Future analyses should seek to clarify the relationship between aetiology, seizure frequency, and degree of memory impairment.

Episodic and semantic memory in mild cognitive impairment.

Little is known about episodic and semantic memory in the early predementia stage of Alzheimer's disease (AD), which is referred to as mild cognitive impairment (MCI). To explore person knowledge, item recognition and spatial associative memory, we designed the Face Place Test (FPT). A total of 75 subjects participated: 22 patients with early AD, 24 with MCI and 29 matched controls. As predicted, AD patients showed significant deficits in person naming, item recognition and recall of spatial location (placing). Surprisingly, subjects with MCI were also impaired on all components. There was no significant difference between AD and MCI except on the placing component. Analysis of the relationship between semantic (naming) and episodic (recognition and placing) components of the FPT revealed a significant association between the two episodic tasks, but not between episodic and semantic performance. Patients with MCI show deficits of episodic and semantic memory. The extent of impairment suggests dysfunction beyond the medial temporal lobe. The FPT might form the basis of a sensitive early indicator of AD.

Multidimensional measures of person knowledge and spatial associative learning: can these be applied to the differentiation of Alzheimer's disease from frontotemporal and vascular dementia?

Patients with early stage Alzheimer's disease (AD) show deficits in person knowledge and spatial associative memory. The current investigation examined the ability of impairment in these domains to differentiate AD from other overlapping conditions. In experiment 1, 14 AD patients, 21 vascular dementia (VaD) patients, 11 frontal variant frontotemporal dementia (fvFTD) patients and 41 controls were administered a graded faces test. VaD patients demonstrated a level of impairment comparable to the AD group on both the naming and person identification elements of the task. A mild naming deficit was revealed in the fvFTD group. In experiment 2, 22 AD patients, 23 patients with mild cognitive impairment (MCI), 11 fvFTD patients, 13 semantic dementia (SD) patients, and 23 elderly controls were administered the face-place test, a newly developed task that combines naming of famous faces, item recognition and spatial location. The naming component of the face-place test clearly differentiated SD patients from all dementia groups. All patient groups, except those with fvFTD, showed substantial deficits in the item recognition and spatial components. Consistency analyses indicated a fairly robust association between the two episodic components (item recognition and placing), but not between semantic and episodic elements of the FPT. Person knowledge deficits are, therefore, not specific to AD and the employment of face stimuli may influence the performance of SD patients on tasks of episodic memory.

Can episodic memory tasks differentiate semantic dementia from Alzheimer's disease?

The performance of two groups of patients with semantic dementia (SD), with predominant right (SDR) and left temporal lobe atrophy (SDL), was contrasted with that of cases with probable Alzheimer's disease (AD) on a range of standard episodic memory tasks. While the SDL group achieved a good score on a composite visual, but not a verbal, episodic memory measure, the AD and SDR groups were equivalently impaired at visual and verbal memory. The SD, but not the AD, groups were, by definition, impaired on simple tests of semantic memory. Standard verbal episodic memory tests, therefore, failed to discriminate patients with SD from those with probable AD and even visual memory tests may result in misclassification of SDR cases.

"Pray or Prey?" dissociation of semantic memory retrieval from episodic memory processes using positron emission tomography and a novel homophone task.

One problem in studying the neural basis of semantic memory using functional neuroimaging is that it is often difficult to disentangle activation associated with semantic memory retrieval from that associated with episodic memory encoding and retrieval. To address this issue, a novel homophone task was used in which subjects were PET scanned whilst learning a series of real words (e.g., prey). In a subsequent scan, the subjects were presented with homophone pairs (e.g., prey vs pray) and were required to choose the one that had been shown previously. In two corresponding baseline tasks, the subjects were scanned whilst learning and recognizing pronounceable nonwords. Thus, while all of these tasks recruited either episodic memory encoding or retrieval processes, only the homophone tasks involved semantic memory retrieval. A conjunction analysis designed to isolate activation associated with semantic memory retrieval, revealed changes in several left lateral frontal regions (BA 9/10, 9/45), the left middle temporal cortex (BA 21), and in the left inferior temporoparietal cortex (BA 39). In contrast, a conjunction analysis designed to isolate activation associated with episodic memory encoding, revealed significant changes in the left hippocampus, as well as in the frontopolar cortex (BA 10) bilaterally, the left inferior parietal cortex (BA 40), and the left superior temporal gyrus (BA 22, 28). The present results clarify and extend recent attempts to understand the neural basis of semantic memory retrieval, by actively controlling for the confounding effects of episodic memory encoding and retrieval processes.

Memory consolidation and the hippocampus: further evidence from studies of autobiographical memory in semantic dementia and frontal variant frontotemporal dementia.

Studies of autobiographical memory in semantic dementia have found relative preservation of memories for recent rather than remote events. As semantic dementia is associated with progressive atrophy to temporal neocortex, with early asymmetric sparing of the hippocampus, this neuropsychological pattern suggests that the hippocampal complex plays a role in the acquisition and retrieval of recent memories, but is not necessary for the recall of older episodic events. In an alternative view of memory consolidation, however, the hippocampus plays a role in the retrieval of all autobiographical memories, regardless of the age of the memory [Curr. Opin. Neurobiol. 7(1997)217]. This 'multiple trace theory' predicts that patients with semantic dementia should show no effects of time in their autobiographical recall. In this article, we ask whether it is possible to reconcile the data from semantic dementia with the multiple trace theory by investigating whether the time-dependent pattern of autobiographical retrieval seen in the disease is due to (i) patients showing this effect being exceptional in their presentation; and/or (ii) patients with semantic dementia exhibiting impaired strategic retrieval from concomitant frontal damage. A series of experiments in patients with semantic dementia, the frontal variant of frontotemporal dementia and Alzheimer's disease clearly demonstrates that neither of these two factors can explain the documented effect of time seen in semantic dementia. Nonetheless, we discuss how damage to semantic knowledge could result in an autobiographical memory deficit and suggest that data from semantic dementia may be consistent with both views of hippocampal involvement in long-term memory.

p22 is a novel plasminogen fragment with antiangiogenic activity.

Tumor or tumor-associated cells cleave circulating plasminogen into three or four kringle-containing antiangiogenic fragments, collectively referred to as angiostatin. Angiostatin blocks tumor growth and metastasis by preventing the growth of endothelial cells that are critical for tumor vascularization. Here, we show that cancer and normal cells convert plasminogen into a novel 22 kDa fragment (p22). Production of this plasminogen fragment in a cell-free system has allowed characterization of the structure and activity of the protein. p22 consists of amino acid residues 78-180 of plasminogen and therefore embodies the first plasminogen kringle (residues 84-162) as well as additional N- and C-terminal residues. Circular dichroism and intrinsic fluorescence spectrum analysis have defined structural differences between p22 and recombinant plasminogen kringle 1 (rK1), therefore suggesting a unique conformation for kringle 1 within p22. Proliferation of capillary endothelial cells but not cells of other lineages was selectively inhibited by p22 in vitro. In addition, p22 prevented vascular growth of chick chorioallantoic membranes (CAMs) in vivo. Furthermore, administration of p22 at low dose suppressed the growth of murine Lewis lung carcinoma (LLC) metastatic foci in vivo. This is the first identification of a single kringle-containing antiangiogenic plasminogen fragment produced under physiological conditions.

Episodic memory: insights from semantic dementia.

Semantic dementia, also known as the temporal lobe variant of fronto-temporal dementia, results in a progressive yet relatively pure loss of semantic knowledge about words, objects and people, and is associated with asymmetric, focal atrophy of the antero-lateral temporal lobes. Semantic dementia provides a unique opportunity to study the organization of long-term memory particularly since initial observations suggested sparing of episodic memory. Recent studies reveal, however, a more complex but theoretically revealing pattern. On tests of autobiographical memory, patients with semantic dementia show a 'reverse step function' with sparing of recall of events from the most recent 2 to 5 years but impairment on more distant life periods. Anterograde recognition memory for visual materials is extremely well preserved, except in the most deteriorated cases, although performance is heavily reliant upon perceptual information about the studied stimuli, particularly for items that are no longer known by the subjects. On tests of verbal anterograde memory such as word learning, performance is typically poor even for words which are 'known' to the patients. A source discrimination experiment, designed to evaluate familiarity and recollection-based anterograde memory processes, found that patients with semantic dementia showed good item detection, although recollection of source was sometimes impaired. Semantic knowledge about studied items and measures of item detection and source discrimination were largely independent. The implications of these findings for models of long-term memory are discussed. The results support the concept that episodic memory, or at least the recall of temporally specific autobiographical experiences, draws upon a number of separable memory processes, some of which can function independently of semantic knowledge.

Perceptual and semantic components of memory for objects and faces: a pet study.

Previous studies have suggested differences in the neural substrates of recognition memory when the contributions of perceptual and semantic information are manipulated. In a within-subjects design PET study, we investigated the neural correlates of the following factors: material type (objects or faces), semantic knowledge (familiar or unfamiliar items), and perceptual similarity at study and test (identical or different pictures). There was consistent material-specific lateralization in frontal and temporal lobe regions when the retrieval of different types of nonverbal stimuli was compared, with objects activating bilateral areas and faces preferentially activating the right hemisphere. Retrieval of memories for nameable, familiar items was associated with increased activation in the left ventrolateral prefrontal cortex, while memory for unfamiliar items involved occipital regions. Recognition memory for different pictures of the same item at study and test produced blood flow increase in left inferior temporal cortex. These results have implications for our understanding of the neural correlates of perceptual and semantic contributions to recognition memory.