Menopause and cognitive complaints: are ovarian hormones linked with subjective cognitive decline?

Subjective cognitive decline (SCD) and the loss of ovarian hormones after menopause have been independently linked to later-life Alzheimer's disease (AD). The objective of this review was to determine whether menopause and the loss of ovarian hormones contribute to cognitive complaints and SCD in women. This would suggest that SCD at the menopausal transition might be an important marker of eventual cognitive decline and AD. We conducted a literature search using PubMed, PsycINFO and Web of Science in July 2020. All English-language studies assessing SCD and cognitive complaints with respect to menopause and ovarian hormones were included. A total of 19 studies were included. Studies found that cognitive complaints increased across the menopause transition and were associated with reductions in attention, verbal and working memory, and medial temporal lobe volume. Women taking estrogen-decreasing treatments also had increased cognitive complaints and reduced working memory and executive function. The current literature provides impetus for further research on whether menopause and the loss of ovarian hormones are associated with cognitive complaints and SCD. Clinicians may take particular note of cognitive complaints after menopause or ovarian hormone loss, as they might presage future cognitive decline.

Real-World Variability in the Prediction of Intracranial Aneurysm Wall Shear Stress: The 2015 International Aneurysm CFD Challenge.

PURPOSE: Image-based computational fluid dynamics (CFD) is widely used to predict intracranial aneurysm wall shear stress (WSS), particularly with the goal of improving rupture risk assessment. Nevertheless, concern has been expressed over the variability of predicted WSS and inconsistent associations with rupture. Previous challenges, and studies from individual groups, have focused on individual aspects of the image-based CFD pipeline. The aim of this Challenge was to quantify the total variability of the whole pipeline. METHODS: 3D rotational angiography image volumes of five middle cerebral artery aneurysms were provided to participants, who were free to choose their segmentation methods, boundary conditions, and CFD solver and settings. Participants were asked to fill out a questionnaire about their solution strategies and experience with aneurysm CFD, and provide surface distributions of WSS magnitude, from which we objectively derived a variety of hemodynamic parameters. RESULTS: A total of 28 datasets were submitted, from 26 teams with varying levels of self-assessed experience. Wide variability of segmentations, CFD model extents, and inflow rates resulted in interquartile ranges of sac average WSS up to 56%, which reduced to < 30% after normalizing by parent artery WSS. Sac-maximum WSS and low shear area were more variable, while rank-ordering of cases by low or high shear showed only modest consensus among teams. Experience was not a significant predictor of variability. CONCLUSIONS: Wide variability exists in the prediction of intracranial aneurysm WSS. While segmentation and CFD solver techniques may be difficult to standardize across groups, our findings suggest that some of the variability in image-based CFD could be reduced by establishing guidelines for model extents, inflow rates, and blood properties, and by encouraging the reporting of normalized hemodynamic parameters.

Varying the importance of a prospective memory task: differential effects across time- and event-based prospective memory.

Only few studies have addressed the issue of task importance in prospective memory. Most of them, but not all, have shown that perceived task importance does improve prospective memory performance. However, there is little understanding of (1) the conditions under which importance of the prospective memory task makes a difference in performance and (2) the mechanisms by which perceived task importance has an effect on prospective memory performance. The present study reports two experiments that manipulate task importance in a time-based and an event-based prospective memory paradigm. Results show that importance has an effect on the time-based but not on the event-based task. Further analyses of the performance in the cover tasks as well as the monitoring behaviour indicate that importance improves prospective memory to the degree the task requires the strategic allocation of attentional resources.

Plan formation, retention, and execution in prospective memory: a new approach and age-related effects.

Existing laboratory paradigms of prospective memory instruct subjects to remember to perform a single, isolated act at an appropriate point in the experiment. These paradigms do not completely capture many everyday complex prospective memory situations in which a series or set of delayed actions is planned to be executed in some subsequent period of time. We adapted a laboratory paradigm within which to study these prospective memory processes, and we investigated age-related influences on these prospective memory processes. Age-related declines were found in the planning, initiation, and execution of the set of tasks. In contrast, there were no age differences in plan retention or in the fidelity with which the plan was performed.

Prospective memory and aging: forgetting intentions over short delays.

Retrieved intentions often cannot be performed immediately and must be maintained until there is an opportunity to perform them. In 3 experiments, on seeing a target event, younger and older participants were to withhold an action until they encountered the appropriate phase of the experiment. When initial retrieval was made facile by the use of a salient retrieval cue, the age-related decrements were often dramatic, even over unfilled delay intervals as brief as 10 s (Experiments 1 and 2). When initial retrieval was difficult, older adults showed no forgetting over the retention interval (Experiment 3). Several theoretical perspectives were offered as explanations for the age differences observed with salient retrieval cues, including those that focus on age differences in metamemory, the degree to which plans are reformulated, and the ability to nonstrategically maintain current concerns in working memory.

Detection of neuritic plaques in Alzheimer's disease by magnetic resonance microscopy.

Magnetic resonance microscopy (MRM) theoretically provides the spatial resolution and signal-to-noise ratio needed to resolve neuritic plaques, the neuropathological hallmark of Alzheimer's disease (AD). Two previously unexplored MR contrast parameters, T2* and diffusion, are tested for plaque-specific contrast to noise. Autopsy specimens from nondemented controls (n = 3) and patients with AD (n = 5) were used. Three-dimensional T2* and diffusion MR images with voxel sizes ranging from 3 x 10(-3) mm(3) to 5.9 x 10(-5) mm(3) were acquired. After imaging, specimens were cut and stained with a microwave king silver stain to demonstrate neuritic plaques. From controls, the alveus, fimbria, pyramidal cell layer, hippocampal sulcus, and granule cell layer were detected by either T2* or diffusion contrast. These structures were used as landmarks when correlating MRMs with histological sections. At a voxel resolution of 5.9 x 10(-5) mm(3), neuritic plaques could be detected by T2*. The neuritic plaques emerged as black, spherical elements on T2* MRMs and could be distinguished from vessels only in cross-section when presented in three dimension. Here we provide MR images of neuritic plaques in vitro. The MRM results reported provide a new direction for applying this technology in vivo. Clearly, the ability to detect and follow the early progression of amyloid-positive brain lesions will greatly aid and simplify the many possibilities to intervene pharmacologically in AD.

Granule cells in aging rats are sexually dimorphic in their response to estradiol.

Normal aging comprises cognitive decline, including deterioration of memory. It has been suggested that this decline in memory is sexually dimorphic because of the cessation in gonadal steroid secretion that occurs during reproductive aging in female, but not male, mammals. We wondered whether neurons in brain regions associated with learning and memory underwent morphological changes that were dimorphic as well and whether cessation of the secretion of gonadal steroids influenced these morphological changes. To explore these questions, we deprived and restored estrogens to young and old gonadectomized females and males and studied the morphology of dentate granule cells by intracellular dye filling in a lightly fixed slice preparation. We found the following: (1) Aged female dentate granule cells deprived of gonadal steroids long-term have a paucity of dendritic spines compared with young females deprived short-term; however, aged male dentate granule cells deprived of gonadal steroids long-term have no decrease in dendritic spines compared with young males deprived short-term. (2) Aged female dentate granule cells with long-term estrogen replacement at either high or low levels still had a decline in spine density. (3) Aged female dentate granule cells with short-term estradiol replacement had spine density increased to levels normally observed in young adults, whereas aged males with short-term estradiol replacement had decreased spine density. These data suggest that the response of rat dentate granule cells to aging and estradiol is sexually dimorphic and that, in females, the responsiveness of granule cells depends on the temporal pattern of estradiol replacement.

Intraneuronal ApoE in human visual cortical areas reflects the staging of Alzheimer disease pathology.

Alzheimer disease (AD) is marked by progressive loss of cortical neurons with associated cognitive decline. Multiple genetic and environmental factors likely contribute to this progressive loss. Such genetic factors include the polymorphic locus (APOE) that encodes apolipoprotein E (apoE). In order to investigate a possible correspondence between cellular localization of apoE and the neuropathology of AD, we examined the distribution of apoE-immunoreactive neurons in visual cortical areas with different apparent susceptibility to AD neuropathology (areas 17-primary sensory, 18-secondary sensory, and inferior temporal-association cortex) at different stages of AD pathology as described by Braak and Braak. We found that intraneuronal apoE was present at all these stages, however, only in visual cortical regions known to be vulnerable to AD. In the late stages, the laminar distribution of apoE-immunoreactivity matched the distribution of other markers of AD pathology, especially modified tau. These data support previous findings that intraneuronal apoE in neocortex is common in aged, nondemented controls and demonstrate that it may be more common in regions at risk for AD pathology. Thus, intraneuronal accumulation of apoE may be an attribute of cortical neurons that are more vulnerable to age-related injury with the presence of apoE antedating the classical indices of late-onset AD pathology.

Prospective memory: when reminders fail.

A frequent assumption in the area of prospective memory is that a reminder to do an activity in the future improves the likelihood of doing the activity. The results of four experiments indicated, however, that the most general version of this assumption is incorrect. Subjects were either reminded of a prospective memory task several times during a retention interval or not reminded of the prospective memory task. The most effective reminders referred both to the prospective memory target events and to the intended activity. Reminders that referred only to the target events did not improve prospective memory (relative to a no-reminder control). Reminders that referred only to the intended activity did improve prospective memory, but not to the level of reminders that referred both to the target events and to the intended activity. Instructions to imagine oneself performing the prospective memory task did not further improve prospective memory. Neither the delay between the prospective memory instructions and the prospective memory cover task nor the delay between a reminder and a prospective memory target event significantly influenced performance. The results, which are discussed in terms of theoretical and practical implications, support a new theory of prospective memory and suggest surprising conditions under which reminders fail to benefit prospective memory.

Prospective remembering: perceptually driven or conceptually driven processes?

Converging experimental operations and several prospective memory tasks were used across three experiments to determine the extent to which prospective remembering is supported by data-driven versus conceptually driven processes. In all experiments, subjects were asked to perform an action when a target item later occurred. When the semantic context changed from encoding to test, prospective memory significantly declined (Experiment 1). When the target event (the item, which in its subsequent appearance in the experiment was the signal to perform the action) was presented as word (relative to picture presentation, Experiment 2) or was encoded nonsemantically (relative to semantic encoding, Experiment 3), there was a decline in prospective memory performance. Dividing attention during prospective memory retrieval substantially reduced prospective memory performance (Experiment 3). The results of this research indicated that prospective memory is largely conceptually driven, and it behaves more similarly to direct rather than indirect conceptual tests. We suggest that prospective remembering of the type studied here is mediated by a reflexive episodic associative memory system as proposed by Moscovitch (1994).

Aging and mind wandering: reduced inhibition in older adults?

Hasher and Zacks (1988) theorize that aging disrupts the efficient operation of an inhibitory mechanism that, when functioning normally, is thought to suppress information irrelevant to one's cognitive goals. Problems with this inhibitory mechanism should produce increased mind wandering, and the present experiment examined this possibility using a performance-based measure of mind wandering. Younger and older participants were presented with a long list of words and were occasionally stopped (at unpredictable intervals) and asked to recall the most recently presented items. Mind wandering was inferred by conditionalizing recall on these unpredictable trials with recall on short, predictable trials (in which, presumably, participants were able to maintain full attention to the recall task). Whereas mind wandering was shown to be higher on longer trials than shorter ones, there was no evidence of age differences in mind wandering.

Aging and prospective memory: the influence of increased task demands at encoding and retrieval.

A feature of prospective memory tasks is that they tend to be embedded into other background activities. Two experiments examined how the demands of these background activities affect age differences in prospective memory. The first experiment showed that increasing the demands of the background activities (by adding a digit-monitoring task) significantly reduced prospective memory performance. Planned comparisons revealed that age differences in prospective memory were reliable only in the more demanding background condition. The second experiment revealed significant prospective memory declines when the demands were selectively increased at encoding for both younger and older adults. When the demands were selectively increased at retrieval, older adults were particularly affected. The authors propose a model that relies on both automatic retrieval processes and working memory resources to explain prospective memory remembering.

Transgeniculate signal transmission to middle suprasylvian cortex in intact cats and following early removal of areas 17 and 18: a morphological study.

Removal of cat areas 17 and 18 early, but not late, in postnatal development results in the sparing of certain reflexive and nonreflexive visually guided behaviors. These spared behaviors are accompanied by an expansion of geniculocortical projections to middle suprasylvian (MS) cortex. However, little is known about the types of visual signals relayed along these pathways. The purpose of our study was to reveal the morphologies of the neurons participating in the rewired circuits and, by relating them to the morphologies of functionally characterized neurons described by others, infer the types of visual signals transmitted via the lateral geniculate nucleus (LGN) to MS cortex. To do this, we retrogradely labeled LGN neurons from MS cortex with fluorescent microspheres, and subsequently intracellularly filled them with Lucifer Yellow. We then classified well-filled neurons according to a battery of morphological parameters (such as soma size and shape, and dendritic field-form and specializations), and compared them with already defined structure/function relationships. By doing this, we found that the large majority of visual thalamic relay neurons to MS cortex of both normal cats and cats that incurred removal of areas 17 and 18 were types I and IV. These results indicate that visual Y and W signals, respectively, are relayed directly from LGN to MS cortex in both types of cats. Following the early lesions, some of the MS-projecting type I neurons were found in layers A and A1, where they are never found in intact cats. Thus, some layer A and A1 type I neurons redirect axons to MS cortex following early removal of areas 17 and 18. For the type IV MS-projecting neurons in early lesioned cats, the somas were hypertrophied and they had more profuse and broader dendritic arbors than equivalent neurons in intact cats. These results suggest that dynamic interactions take place between inputs and outputs of LGN neurons during development that influence final LGN neuron morphology. Moreover, they suggest that signals transferred to MS cortex by type IV neurons may be modified by early lesions of areas 17 and 18. Overall, these results contribute to our understanding of the types of behaviors that may be spared by early lesions of areas 17 and 18.

Is binding to nicotinic acetylcholine and dopamine receptors related to working memory in rats?

Nicotinic acetylcholine (ACh) and dopamine (DA) receptor activation has been found to be important for working memory. The regional distribution of these receptors in the brain has been well characterized. However, the relationship of the region-specific nicotinic ACh and DA binding density to memory performance has not been well assessed. In the current studies the relationship of receptor binding and memory function was examined. Receptor binding and memory performance were assessed in rats in three types of conditions: 1) chronic nicotine and mecamylamine vs. vehicle infusion; 2) lesions of the fimbria-fornix or medial basalocortical projection vs. sham lesions; and 3) 2-year-old aged rats vs. 3-month-old young adult rats. Nicotinic ACh receptors were labeled by [3H]N-methyl-carbamylcholine ([3H]MCC), D1 receptors by [3H]SCH 23390, and D2 receptors by [125I]iodosulpiride. Working memory was assessed using the radial-arm maze and T-maze delayed spatial alternation tasks. Chronic nicotine infusion substantially increased nicotinic receptor binding in a variety of brain areas and significantly improved working memory performance in the radial-arm maze. However, nicotinic receptor binding did not correlate well with memory performance. The nicotinic antagonist mecamylamine did not block nicotine-induced increased nicotinic binding, but it did block nicotine-induced memory improvement. Aged rats relative to young adults showed both a decrease in nicotinic binding and impaired memory performance. However, chronic effects of nicotine on nicotinic receptor binding and memory performance did not correlate in the aged rats. Nicotine also increased nicotinic receptor binding in the aged rats in brain areas except for the VTA, but did not improve memory performance. Lesions of the medial basalocortical projection or the fimbria-fornix did not cause significant changes in nicotinic binding in their target fields, but they did cause significant deficits in memory performance. Finally, there were no significant correlations of nicotinic binding in any brain region and memory performance. DA receptor binding was not altered by chronic nicotine or mecamylamine infusion, fimbria-fornix lesions, medial basalocortical lesions, or in aged rats. However, DA receptor binding did correlate with memory performance. There was a positive correlation of T-maze accuracy and D1 receptor binding in the frontal cortex and a negative correlation of T-maze accuracy and D1 receptor binding in the VTA and dentate gyrus. In contrast, a positive correlation was seen between radial-arm maze accuracy and D1 receptor binding in the VTA. Radial-arm maze accuracy was positively correlated with D2 receptor binding in the striatum and dentate gyrus. There are significant relationships between the extent of DA receptor binding and working memory, but relationship between nicotinic ACh receptor binding density and memory is weak.

Reciprocal projections of cat extrastriate cortex: I. Distribution and morphology of neurons projecting from posterior medial lateral suprasylvian sulcus to area 17.

Reciprocal projections between cortical areas have been subdivided into two functionally distinct component, "feedforward" and "feedback" (for review, see Felleman and Van Essen [1991] Cereb. Cortex 1:1-47). Some anatomical evidence, such as differences in the laminar distribution of the neurons of origin and of the terminations of their axons, has supported this division. However, very little is actually known about the distribution and morphology of the neurons of the feedback projections. In order to contribute further to our understanding of these two components of the corticocortical projections, I studied the distribution and morphology of a feedback projection, the reciprocal projection from the posterior medial lateral suprasylvian sulcus (PMLS), to primary visual cortex (area 17). Retrograde transport of horseradish peroxidase and fluorescent tracers in vivo combined with intracellular dye injections in lightly fixed cortical slices revealed many similarities between the feedforward and feedback projections: 1) They both emanate from all layers but layer 1; 2) each layer of origin contains a wide variety of standard and/or inverted pyramidal neurons; and 3) all of these, with the exception of a rare, large layer 5 neuron, have dendritic fields restricted principally to their layers of origin. There was, however, one major difference between the feedforward and feedback projections: In contrast to the projection from area 17 to PMLS, the projection from PMLS had a dense projection from layer 6 that compromised a striking abundance of spiny fusiform and inverted pyramidal neurons. These were morphologically distinct from other layer 6 neurons that project to the thalamus. Taken together, these data suggest that the reciprocal projections between area 17 and area PMLS, although not completely equivalent, share essential features that form a distinct population of neurons differing in morphology from corticothalamic projection neurons.

Microglia are not exclusively associated with plaque-rich regions of the dentate gyrus in Alzheimer's disease.

The functional significance of microglia found in neuritic plaques in Alzheimer's disease (AD) remains a source of controversy. In the present study, we explored the anatomic relationships between microglia and neuritic plaques in order to determine the potential role of microglia in plaque formation. We chose to study the molecular layer of the hippocampal dentate gyrus, a brain region where plaques have a strong tendency to line up parallel to the adjacent granule cell layer. We found that ferritin-labeled microglia were indeed most numerous in the same distinct band as plaques, but that microglia were relatively more common in the outer molecular layer. The distribution of microglia was more variable than that of plaques. Overall, microglial cell distribution was a relatively poor predictor of plaque distribution, particularly when cases were considered individually. Thus, there must be multiple triggers for microglial cell activation and accumulation in the AD brain, triggers which do not all necessarily lead to neuritic plaque formation.

Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism.

There are two distinct viewpoints on the association of the inheritance of apolipoprotein E (APOE) alleles and the age of onset distribution of Alzheimer's disease (AD): genetic and phenotypic expression. There have been multiple corroborations of the APOE-epsilon 4 association with Alzheimer's disease in populations around the world in clinic based studies as well as emerging epidemiological studies. The genetic data do not imply mechanism of pathogenesis. The phenotypic expression of AD has been based in theories based on amyloid plaques or neurofibrillary tangles. ApoE protein interacts with both beta-amyloid and tau in an isoform-specific manner. The interaction with tau had been thought to be an in vitro artifact, since apoE had not been previously localized to the neuronal cytoplasm. Immuno-EM studies have localized apoE in neuronal cytoplasm. ApoE3 interacts with both tau and MAP2c at the microtubule binding repeat domain under conditions in which apoE4 is less tightly bound. These data further support a hypothesis that apoE3 (and apoE2) protect the microtubule binding domain of tau from binding to itself to form paired helical filaments and neurofibrillary tangles, while protecting the site for microtubule stabilizing interactions with beta-tubulin. These data are supported by recent data from APOE knock-out mice demonstrating dendritic alterations leading to synaptic simplification similar to that observed in AD.

Aging and prospective memory: examining the influences of self-initiated retrieval processes.

Past research has frequently failed to find age differences in prospective memory. This article tested the possibility that age differences would be more likely to emerge on a prospective memory task that was high in self-initiated retrieval. In the 1st experiment, participants were asked to perform an action every 10 min (a time-based task presumed to be high in self-initiated retrieval); in the 2nd experiment, participants were asked to perform an action whenever a particular word was presented (an event-based task presumed to be relatively low in self-initiated retrieval). Age differences were found with the time-based task but not with the event-based task. This pattern of age differences was again found in a 3rd experiment in which a new experimental procedure was used and the nature of the prospective memory task was directly varied. Generally, the results suggest that self-initiated retrieval processes are an important component of age-related differences across both retrospective and prospective memory tasks.

Influence of the susceptibility genes apolipoprotein E-epsilon 4 and apolipoprotein E-epsilon 2 on the rate of disease expressivity of late-onset Alzheimer's disease.

Apolipoprotein E-epsilon 4 (APOE4, gene; apoE4, protein) is a susceptibility gene or risk factor for Alzheimer's disease. The genetic relevance of APOE4 has been widely confirmed. The APOE gene is not a disease locus, with specific mutations causing Alzheimer disease. Allelic variations at the APOE locus affect the rate of disease progression. The association of specific inherited APOE alleles with age of onset distributions describes biological effects based on genotype. The inheritance of polymorphic genes with single amino acid differences between apoE4 and apoE3 (and between apoE3 and apoE2) at the protein level is associated with differences in the mean age of disease onset spanning almost two decades. The isoform-specific metabolism of apoE resulting in a faster rate of disease expression can now be studied with the expectation that genetically relevant processes are being investigated. There is now an opportunity to develop theories directed at the genetically relevant apoE metabolism that can significantly delay disease expression.