Prospective Effects of Self-Rated Health on Dementia Risk in Two Twin Studies of Aging.

Subjective health ratings are associated with dementia risk such that those who rate their health more poorly have increased risk for dementia. The genetic and environmental mechanisms underlying this association are unclear, as prior research cannot rule out whether the association is due to genetic confounds. The current study addresses this gap in two samples of twins, one from Sweden (N = 548) and one from Denmark (N = 4,373). Using genetically-informed, bivariate regression models, we assessed whether additive genetic effects explained the association between subjective health and dementia risk as indexed by a latent variable proxy measure. Age at intake, sex, education, depressive symptomatology, and follow-up time between subjective health and dementia risk assessments were included as covariates. Results indicate that genetic variance and other sources of confounding accounted for the majority of the effect of subjective health ratings on dementia risk. After adjusting for genetic confounding and other covariates, a small correlation was observed between subjective health and latent dementia risk in the Danish sample (rE = - .09, p < .05). The results provide further support for the genetic association between subjective health and dementia risk, and also suggest that subjective ratings of health measures may be useful for predicting dementia risk.

Remember This: Age Moderation of Genetic and Environmental Contributions to Verbal Episodic Memory from Midlife through Late Adulthood.

It is well documented that memory is heritable and that older adults tend to have poorer memory performance than younger adults. However, whether the magnitudes of genetic and environmental contributions to late-life verbal episodic memory ability differ from those at earlier ages remains unresolved. Twins from 12 studies participating in the Interplay of Genes and Environment in Multiple Studies (IGEMS) consortium constituted the analytic sample. Verbal episodic memory was assessed with immediate word list recall (N = 35,204 individuals; 21,792 twin pairs) and prose recall (N = 3,805 individuals; 2,028 twin pairs), with scores harmonized across studies. Average test performance was lower in successively older age groups for both measures. Twin models found significant age moderation for both measures, with total inter-individual variance increasing significantly with age, although it was not possible definitively to attribute the increase specifically to either genetic or environmental sources. Pooled results across all 12 studies were compared to results where we successively dropped each study (leave-one-out) to assure results were not due to an outlier. We conclude the models indicated an overall increase in variance for verbal episodic memory that was driven by a combination of increases in the genetic and nonshared environmental parameters that were not independently statistically significant. In contrast to reported results for other cognitive domains, differences in environmental exposures are comparatively important for verbal episodic memory, especially word list learning.

Bruch's Membrane Calcification in Pseudoxanthoma Elasticum: Comparing Histopathology and Clinical Imaging.

Purpose: To investigate the histology of Bruch's membrane (BM) calcification in pseudoxanthoma elasticum (PXE) and correlate this to clinical retinal imaging. Design: Experimental study with clinicopathological correlation. Subjects and Controls: Six postmortem eyes from 4 PXE patients and 1 comparison eye from an anonymous donor without PXE. One of the eyes had a multimodal clinical image set for comparison. Methods: Calcification was labeled with OsteSense 680RD, a fluorescent dye specific for hydroxyapatite, and visualized with confocal microscopy. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy (SEM-EDX) and time-of-flight secondary ion mass spectrometry (TOF-SIMs) were used to analyze the elemental and ionic composition of different anatomical locations. Findings on cadaver tissues were compared with clinical imaging of 1 PXE patient. Main Outcome Measures: The characteristics and topographical distribution of hydroxyapatite in BM in eyes with PXE were compared with the clinical manifestations of the disease. Results: Analyses of whole-mount and sectioned PXE eyes revealed an extensive, confluent OsteoSense labeling in the central and midperipheral BM, transitioning to a speckled labeling in the midperiphery. These areas corresponded to hyperreflective and isoreflective zones on clinical imaging. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy and TOF-SIMs analyses identified these calcifications as hydroxyapatite in BM of PXE eyes. The confluent fluorescent appearance originates from heavily calcified fibrous structures of both the collagen and the elastic layers of BM. Calcification was also detected in an aged comparison eye, but this was markedly different from PXE eyes and presented as small snowflake-like deposits in the posterior pole. Conclusions: Pseudoxanthoma elasticum eyes show extensive hydroxyapatite deposition in the inner and outer collagenous and elastic BM layers in the macula with a gradual change toward the midperiphery, which seems to correlate with the clinical phenotype. The snowflake-like calcification in BM of an aged comparison eye differed markedly from the extensive calcification in PXE. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Gaze differences in configural and elemental evaluation during multi-attribute decision-making.

Introduction: While many everyday choices are between multi-attribute options, how attribute values are integrated to allow such choices remains unclear. Recent findings suggest a distinction between elemental (attribute-by-attribute) and configural (holistic) evaluation of multi-attribute options, with different neural substrates. Here, we asked if there are behavioral or gaze pattern differences between these putatively distinct modes of multi-attribute decision-making. Methods: Thirty-nine healthy men and women learned the monetary values of novel multi-attribute pseudo-objects (fribbles) and then made choices between pairs of these objects while eye movements were tracked. Value was associated with individual attributes in the elemental condition, and with unique combinations of attributes in the configural condition. Choice, reaction time, gaze fixation time on options and individual attributes, and within- and between-option gaze transitions were recorded. Results: There were systematic behavioral differences between elemental and configural conditions. Elemental trials had longer reaction times and more between-option transitions, while configural trials had more within-option transitions. The effect of last fixation on choice was more pronounced in the configural condition. Discussion: We observed differences in gaze patterns and the influence of last fixation location on choice in multi-attribute value-based choices depending on how value is associated with those attributes. This adds support for the claim that multi-attribute option values may emerge either elementally or holistically, reminiscent of similar distinctions in multi-attribute object recognition. This may be important to consider in neuroeconomics research that involve visually-presented complex objects.

Exploring reward-related attention selectivity deficits in Parkinson's disease.

An important aspect of managing a limited cognitive resource like attention is to use the reward value of stimuli to prioritize the allocation of attention to higher-value over lower-value stimuli. Recent evidence suggests this depends on dopaminergic signaling of reward. In Parkinson's disease, both reward sensitivity and attention are impaired, but whether these deficits are directly related to one another is unknown. We tested whether Parkinson's patients use reward information when automatically allocating their attention and whether this is modulated by dopamine replacement. We compared patients, tested both ON and OFF dopamine replacement medication, to older controls using a standard attention capture task. First, participants learned the different reward values of stimuli. Then, these reward-associated stimuli were used as distractors in a visual search task. We found that patients were generally distracted by the presence of the distractors but that the degree of distraction caused by the high-value and low-value distractors was similar. Furthermore, we found no evidence to support the possibility that dopamine replacement modulates the effect of reward on automatic attention allocation. Our results suggest a possible inability in Parkinson's patients to use the reward value of stimuli when automatically allocating their attention, and raise the possibility that reward-driven allocation of resources may affect the adaptive modulation of other cognitive processes.

Characterization of Calcium Phosphate Spherical Particles in the Subretinal Pigment Epithelium-Basal Lamina Space in Aged Human Eyes.

Purpose: Micrometer-sized spherules formed of hydroxyapatite or whitlockite were identified within extracellular deposits that accumulate in the space between the basal lamina (BL) of retinal pigment epithelium (RPE) and the inner collagenous layer of Bruch's membrane (sub-RPE-BL space). This investigation aimed to characterize the morphologic features, structure, and distribution of these spherules in aged human eyes with and without clinical indications of age-related macular degeneration (AMD). Design: Experimental study. Participants: Five human eyes with varying degrees of sub-RPE-BL deposits were obtained from the University College London Institute of Ophthalmology and Moorfield's Eye Hospital Tissue Repository or the Advancing Sight Network. Two eyes were reported as having clinical indications of AMD (age, 76-87 years), whereas 3 were considered healthy (age, 69-91 years). Methods: Cadaveric eyes with sub-RPE-BL deposits were embedded in paraffin wax and sectioned to a thickness of 4-10 µm. Spherules were identified and characterized using high-resolution scanning electron microscopy (SEM), energy-dispersive x-ray spectroscopy, and time-of-flight secondary ion mass spectroscopy. Main Outcome Measures: High-resolution scanning electron micrographs of spherules, the size-frequency distribution of spherules including average diameter, and the distribution of particles across the central-peripheral axis. Elemental maps and time-of-flight secondary ion mass spectra also were obtained. Results: The precipitation of spherules is ubiquitous across the central, mid-peripheral, and far-peripheral axis in aged human eyes. No significant difference was found in the frequency of spherules along this axis. However, statistical analysis indicated that spherules exhibited significantly different sizes in these regions. In-depth analysis revealed that spherules in the sub-RPE-BL space of eyes with clinical signs of AMD were significantly larger (median diameter, 1.64 µm) than those in healthy aged eyes (median diameter, 1.16 µm). Finally, spherules showed great variation in surface topography and internal structure. Conclusions: The precipitation of spherules in the sub-RPE-BL space is ubiquitous across the central-peripheral axis in aged human eyes. However, a marked difference exists in the size and frequency of spherules in eyes with clinical signs of AMD compared to those without, suggesting that the size and frequency of spherules may be associated with AMD.

A Genetically Informed Longitudinal Study of Loneliness and Dementia Risk in Older Adults.

Although several studies have shown small longitudinal associations between baseline loneliness and subsequent dementia risk, studies rarely test whether change in loneliness predicts dementia risk. Furthermore, as both increase with advancing age, genetic and environmental selection processes may confound the putative causal association between loneliness and dementia risk. We used a sample of 2,476 individual twins from three longitudinal twin studies of aging in the Swedish Twin Registry to test the hypothesis that greater positive change in loneliness predicts greater dementia risk. We then used a sample of 1,632 pairs of twins to evaluate the hypothesis that effects of change in loneliness on dementia risk would remain after adjusting for effects of genetic and environmental variance. Phenotypic model results suggest that mild levels of baseline loneliness predict greater dementia risk. Contrary to our hypothesis, change in loneliness did not correlate with dementia risk, regardless of whether genetic and environmental selection confounds were taken into account. Worsening loneliness with age may not confer greater dementia risk.

On the origin of proteins in human drusen: The meet, greet and stick hypothesis.

Retinal drusen formation is not only a clinical hallmark for the development of age-related macular degeneration (AMD) but also for other disorders, such as Alzheimer's disease and renal diseases. The initiation and growth of drusen is poorly understood. Attention has focused on lipids and minerals, but relatively little is known about the origin of drusen-associated proteins and how they are retained in the space between the basal lamina of the retinal pigment epithelium and the inner collagenous layer space (sub-RPE-BL space). While some authors suggested that drusen proteins are mainly derived from cellular debris from processed photoreceptor outer segments and the RPE, others suggest a choroidal cell or blood origin. Here, we reviewed and supplemented the existing literature on the molecular composition of the retina/choroid complex, to gain a more complete understanding of the sources of proteins in drusen. These "drusenomics" studies showed that a considerable proportion of currently identified drusen proteins is uniquely originating from the blood. A smaller, but still large fraction of drusen proteins comes from both blood and/or RPE. Only a small proportion of drusen proteins is uniquely derived from the photoreceptors or choroid. We next evaluated how drusen components may "meet, greet and stick" to each other and/or to structures like hydroxyapatite spherules to form macroscopic deposits in the sub-RPE-BL space. Finally, we discuss implications of our findings with respect to the previously proposed homology between drusenogenesis in AMD and plaque formation in atherosclerosis.

Calcified nodules in retinal drusen are associated with disease progression in age-related macular degeneration.

Drusen are lipid-, mineral-, and protein-containing extracellular deposits that accumulate between the basal lamina of the retinal pigment epithelium (RPE) and Bruch's membrane (BrM) of the human eye. They are a defining feature of age-related macular degeneration (AMD), a common sight-threatening disease of older adults. The appearance of heterogeneous internal reflectivity within drusen (HIRD) on optical coherence tomography (OCT) images has been suggested to indicate an increased risk of progression to advanced AMD. Here, in a cohort of patients with AMD and drusen, we show that HIRD indicated an increased risk of developing advanced AMD within 1 year. Using multimodal imaging in an independent cohort, we demonstrate that progression to AMD was associated with increasing degeneration of the RPE overlying HIRD. Morphological analysis of clinically imaged cadaveric human eye samples revealed that HIRD was formed by multilobular nodules. Nanoanalytical methods showed that nodules were composed of hydroxyapatite and that they differed from spherules and BrM plaques, other refractile features also found in the retinas of patients with AMD. These findings suggest that hydroxyapatite nodules may be indicators of progression to advanced AMD and that using multimodal clinical imaging to determine the composition of macular calcifications may help to direct therapeutic strategies and outcome measures in AMD.

Subretinal Pigment Epithelial Deposition of Drusen Components Including Hydroxyapatite in a Primary Cell Culture Model.

Purpose: Extracellular deposits containing hydroxyapatite, lipids, proteins, and trace metals that form between the basal lamina of the RPE and the inner collagenous layer of Bruch's membrane are hallmarks of early AMD. We examined whether cultured RPE cells could produce extracellular deposits containing all of these molecular components. Methods: Retinal pigment epithelium cells isolated from freshly enucleated porcine eyes were cultured on Transwell membranes for up to 6 months. Deposit composition and structure were characterized using light, fluorescence, and electron microscopy; synchrotron x-ray diffraction and x-ray fluorescence; secondary ion mass spectroscopy; and immunohistochemistry. Results: Apparently functional primary RPE cells, when cultured on 10-µm-thick inserts with 0.4-µm-diameter pores, can produce sub-RPE deposits that contain hydroxyapatite, lipids, proteins, and trace elements, without outer segment supplementation, by 12 weeks. Conclusions: The data suggest that sub-RPE deposit formation is initiated, and probably regulated, by the RPE, as well as the loss of permeability of the Bruch's membrane and choriocapillaris complex associated with age and early AMD. This cell culture model of early AMD lesions provides a novel system for testing new therapeutic interventions against sub-RPE deposit formation, an event occurring well in advance of the onset of vision loss.