Lok-Kin Yeung

White Matter Hyperintensities and Cognition: Testing the Reserve Hypothesis

OBJECTIVE White matter hyperintensities (WMH), visualized on T2-weighted MRI, are thought to reflect small-vessel vascular disease. Much like other markers of brain disease, the association between WMH and cognition is imperfect. The concept of reserve may account for this imperfect relationship. The purpose of this study was to test the reserve hypothesis in the association between WMH severity and cognition. We hypothesized that individuals with higher amounts of reserve would be able to tolerate greater amounts of pathology than those with lower reserve. METHODS Neurologically healthy older adults (n=717) from a community-based study received structural MRI, neuropsychological assessment, and evaluation of reserve. WMH volume was quantified algorithmically. We derived latent constructs representing four neuropsychological domains, a measure of cognitive reserve, and a measure of brain reserve. Measures of cognitive and brain reserve consisted of psychosocial (e.g., education) and anthropometric (e.g., craniometry) variables, respectively. RESULTS Increased WMH volume was associated with poorer cognition and higher cognitive and brain reserve were associated with better cognition. Controlling for speed/executive function or for language function, those with higher estimates of cognitive reserve had significantly greater degrees of WMH volume, particularly among women. Controlling for cognitive functioning across all domains, individuals with higher estimates of brain reserve had significantly greater WMH volume. CONCLUSIONS For any given level of cognitive function, those with higher reserve had more pathology in the form of WMH, suggesting that they are better able to cope with pathology than those with lower reserve. Both brain reserve and cognitive reserve appear to mitigate the impact of pathology on cognition.

The hippocampus and visual perception

In this review, we will discuss the idea that the hippocampus may be involved in both memory and perception, contrary to theories that posit functional and neuroanatomical segregation of these processes. This suggestion is based on a number of recent neuropsychological and functional neuroimaging studies that have demonstrated that the hippocampus is involved in the visual discrimination of complex spatial scene stimuli. We argue that these findings cannot be explained by long-term memory or working memory processing or, in the case of patient findings, dysfunction beyond the medial temporal lobe (MTL). Instead, these studies point toward a role for the hippocampus in higher-order spatial perception. We suggest that the hippocampus processes complex conjunctions of spatial features, and that it may be more appropriate to consider the representations for which this structure is critical, rather than the cognitive processes that it mediates.

Intact memory for irrelevant information impairs perception in amnesia

Summary Memory and perception have long been considered separate cognitive processes, and amnesia resulting from medial temporal lobe (MTL) damage is thought to reflect damage to a dedicated memory system. Recent work has questioned these views, suggesting that amnesia can result from impoverished perceptual representations in the MTL, causing an increased susceptibility to interference. Using a perceptual matching task for which fMRI implicated a specific MTL structure, the perirhinal cortex, we show that amnesics with MTL damage including the perirhinal cortex, but not those with damage limited to the hippocampus, were vulnerable to object-based perceptual interference. Importantly, when we controlled such interference, their performance recovered to normal levels. These findings challenge prevailing conceptions of amnesia, suggesting that effects of damage to specific MTL regions are better understood not in terms of damage to a dedicated declarative memory system, but in terms of impoverished representations of the stimuli those regions maintain.

Brain Tissue Volume Changes Following Weight Gain in Adults with Anorexia Nervosa

OBJECTIVE To measure brain volume deficits among underweight patients with anorexia nervosa (AN) compared to control participants and evaluate the reversibility of these deficits with short-term weight restoration. METHOD Brain volume changes in gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) were examined in 32 adult women with AN and compared to 21, age and body mass index-range matched control women. RESULTS Patients with AN had a significant increase in GM (p = .006, η(2) = 0.14) and WM volume (p = .001, η(2) = 0.19) following weight restoration. Patients on average had lower levels of GM at low weight (647.63 ± 62.07 ml) compared to controls (679.93 ± 53.31 ml), which increased with weight restoration (662.64 ± 69.71 ml), but did not fully normalize. DISCUSSION This study suggests that underweight adult patients with AN have reduced GM and WM volumes that increase with short-term weight restoration.

Quantitative approaches for assessment of white matter hyperintensities in elderly populations

White matter hyperintensities (WMH) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI), including fluid attenuated inverse recovery sequences. Total and regional WMH burden (i.e., volume or severity) has been associated with myriad cognitive, neurological, and psychiatric conditions among older adults. In the current report, we illustrate two approaches to quantify periventricular, deep, and total WMH and examine their reliability and criterion validity among 28 elderly patients enrolled in a depression treatment trial. The first approach, an operator-driven quantitative approach, involves visual inspection of individual MRI scans and manual labeling using a three-step series of procedures. The second approach, a fully automated quantitative approach, uses a processing stream that involves image segmentation, voxel intensity thresholding, and seed growing to label WMH and calculate their volume automatically. There was good agreement in WMH quantification between the two approaches (Cronbachs alpha values from 0.835 to 0.968). Further, severity of WMH was significantly associated with worse depression and increased age, and these associations did not differ significantly between the two quantification approaches. We provide evidence for good reliability and criterion validity for two approaches for WMH volume determination. The operator-driven approach may be better suited for smaller studies with highly trained raters, whereas the fully automated quantitative approach may be more appropriate for larger, high-throughput studies.

Recognition memory impairments caused by false recognition of novel objects

A fundamental assumption underlying most current theories of amnesia is that memory impairments arise because previously studied information either is lost rapidly or is made inaccessible (i.e., the old information appears to be new). Recent studies in rodents have challenged this view, suggesting instead that under conditions of high interference, recognition memory impairments following medial temporal lobe damage arise because novel information appears as though it has been previously seen. Here, we developed a new object recognition memory paradigm that distinguished whether object recognition memory impairments were driven by previously viewed objects being treated as if they were novel or by novel objects falsely recognized as though they were previously seen. In this indirect, eyetracking-based passive viewing task, older adults at risk for mild cognitive impairment showed false recognition to high-interference novel items (with a significant degree of feature overlap with previously studied items) but normal novelty responses to low-interference novel items (with a lower degree of feature overlap). The indirect nature of the task minimized the effects of response bias and other memory-based decision processes, suggesting that these factors cannot solely account for false recognition. These findings support the counterintuitive notion that recognition memory impairments in this memory-impaired population are not characterized by forgetting but rather are driven by the failure to differentiate perceptually similar objects, leading to the false recognition of novel objects as having been seen before.

Human anterolateral entorhinal cortex volumes are associated with cognitive decline in aging prior to clinical diagnosis

We investigated whether older adults without subjective memory complaints, but who present with cognitive decline in the laboratory, demonstrate atrophy in medial temporal lobe (MTL) subregions associated with Alzheimers disease. Forty community-dwelling older adults were categorized based on Montreal Cognitive Assessment (MoCA) performance. Total gray/white matter, cerebrospinal fluid, and white matter hyperintensity load were quantified from whole-brain T1-weighted and fluid-attenuated inversion recovery magnetic resonance imaging scans, whereas hippocampal subfields and MTL cortical subregion volumes (CA1, dentate gyrus/CA2/3, subiculum, anterolateral and posteromedial entorhinal, perirhinal, and parahippocampal cortices) were quantified using high-resolution T2-weighted scans. Cognitive status was evaluated using standard neuropsychological assessments. No significant differences were found in the whole-brain measures. However, MTL volumetry revealed that anterolateral entorhinal cortex (alERC) volume-the same region in which Alzheimers pathology originates-was strongly associated with MoCA performance. This is the first study to demonstrate that alERC volume is related to cognitive decline in undiagnosed community-dwelling older adults.

Anterolateral entorhinal cortex volume predicted by altered intra-item configural processing

Recent functional imaging studies have proposed that the human entorhinal cortex (ERC) is subdivided into functionally distinct anterolateral (alERC) and posteromedial (pmERC) subregions. The alERC overlaps with regions that are affected earliest by Alzheimers disease pathology, yet its cognitive function remains poorly understood. Previous human fMRI studies have focused on its role in object memory, but rodent studies on the putatively homologous lateral entorhinal cortex suggest that it also plays an important role in representing spatial properties of objects. To investigate the cognitive effects of human alERC volume differences, we developed an eye-tracking-based task to evaluate intra-item configural processing (i.e., processing the arrangement of an objects features) and used manual segmentation based on a recently developed protocol to delineate the alERC/pmERC and other medial temporal lobe (MTL) subregions. In a group of older adult men and women at varying stages of brain atrophy and cognitive decline, we found that intra-item configural processing, regardless of an objects novelty, was strongly predicted by alERC volume, but not by the volume of any other MTL subregion. These results provide the first evidence that the human alERC plays a role in supporting a distinct aspect of object processing, namely attending to the arrangement of an objects component features. SIGNIFICANCE STATEMENT Alzheimers disease pathology appears earliest in brain regions that overlap with the anterolateral entorhinal cortex (alERC). However, the cognitive role of the alERC is poorly understood. Previous human studies treat the alERC as an extension of the neighboring perirhinal cortex, supporting object memory. Animal studies suggest that the alERC may support the spatial properties of objects. In a group of older adult humans at the earliest stages of cognitive decline, we show here that alERC volume selectively predicted configural processing (attention to the spatial arrangement of an objects parts). This is the first study to demonstrate a cognitive role related to alERC volume in humans. This task can be adapted to serve as an early detection method for Alzheimers disease pathology.

Human anterolateral entorhinal cortex volumes are associated with preclinical cognitive decline

We investigated whether older adults without subjective memory complaints, but who present with cognitive decline in the laboratory, demonstrate atrophy in medial temporal lobe (MTL) subregions associated with Alzheimers disease. Forty community-dwelling older adults were categorized based on Montreal Cognitive Assessment (MoCA) performance. Total grey/white matter, cerebrospinal fluid, and white matter hyperintensity load were quantified from whole-brain T1-weighted and FLAIR magnetic resonance imaging scans, while hippocampal subfields and MTL cortical subregion volumes (CA1, dentate gyrus/CA2/3, subiculum, anterolateral and posteromedial entorhinal, perirhinal, and parahippocampal cortices) were quantified using high-resolution T2-weighted scans. Cognitive status was evaluated using standard neuropsychological assessments. No significant differences were found in the whole-brain measures. However, MTL volumetry revealed that anterolateral entorhinal cortex (alERC) volume -- the same region in which Alzheimers pathology originates -- was strongly associated with MoCA performance. This is the first study to demonstrate that alERC volume is related to cognitive decline in preclinical, community-dwelling older adults.

Object-in-Place Memory Predicted by Anterolateral Entorhinal Cortex and Parahippocampal Cortex Volume in Older Adults

The lateral portion of the entorhinal cortex is one of the first brain regions affected by tau pathology, an important biomarker for Alzheimer’s disease (AD). Improving our understanding of this region’s cognitive role may help identify better cognitive tests for early detection of AD. Based on its functional connections, we tested the idea that the human anterolateral entorhinal cortex (alERC) may play a role in integrating spatial information into object representations. We recently demonstrated that the volume of the alERC was related to processing the spatial relationships of the features within an object (Yeung et al., 2017). In the present study, we investigated whether the human alERC might also play a role in processing the spatial relationships between an object and its environment using an eyetracking task that assessed visual fixations to a critical object within a scene. Guided by rodent work, we measured both object-in-place memory, the association of an object with a given context (Wilson et al., 2013), and object-trace memory, the memory for the former location of objects (Tsao, Moser, & Moser, 2013). In a group of older adults with varying stages of brain atrophy and cognitive decline, we found that the volume of the alERC and the volume of the parahippocampal cortex (PHC) selectively predicted object-in-place memory, but not object-trace memory. These results provide support for the notion that the alERC may integrate spatial information into object representations.