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Background Cerebral small vessel disease is associated with higher ratios of soluble‐epoxide hydrolase derived linoleic acid diols (12,13‐dihydroxyoctadecenoic acid [DiHOME] and 9,10‐DiHOME) to their parent epoxides (12(13)‐epoxyoctadecenoic acid [EpOME] and 9(10)‐EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra‐high‐performance liquid chromatography–mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13‐DiHOME/12(13)‐EpOME ratio (β=0.251, P =0.023). The 12,13‐DiHOME/12(13)‐EpOME ratio was associated with more lacunes (β=0.266, P =0.028) but not with large vessel stroke volumes. Ratios of 12,13‐DiHOME/12(13)‐EpOME and 9,10‐DiHOME/9(10)‐EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P P P =0.011; β=0.314, P =0.006). In small vessel stroke, the 12,13‐DiHOME/12(13)‐EpOME ratio was associated with higher white matter free water diffusion (β=0.439, P =0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10‐DiHOME/9(10)‐EpOME ratio was associated with temporal lobe atrophy (β=−0.277, P =0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble‐epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular‐glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.

Background Remote health monitoring with wearable sensor technology may positively impact patient self-management and clinical care. In individuals with complex health conditions, multi-sensor wear may yield meaningful information about health-related behaviors. Despite available technology, feasibility of device-wearing in daily life has received little attention in persons with physical or cognitive limitations. This mixed methods study assessed the feasibility of continuous, multi-sensor wear in persons with cerebrovascular (CVD) or neurodegenerative disease (NDD). Methods Thirty-nine participants with CVD, Alzheimer’s disease/amnestic mild cognitive impairment, frontotemporal dementia, Parkinson’s disease, or amyotrophic lateral sclerosis (median age 68 (45–83) years, 36% female) wore five devices (bilateral ankles and wrists, chest) continuously for a 7-day period. Adherence to device wearing was quantified by examining volume and pattern of device removal (non-wear). A thematic analysis of semi-structured de-brief interviews with participants and study partners was used to examine user acceptance. Results Adherence to multi-sensor wear, defined as a minimum of three devices worn concurrently, was high (median 98.2% of the study period). Non-wear rates were low across all sensor locations (median 17–22 min/day), with significant differences between some locations (p = 0.006). Multi-sensor non-wear was higher for daytime versus nighttime wear (p

Background: Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical atrophy to NPS in participants across neurodegenerative and cerebrovascular diseases. Methods: 513 participants with one of these conditions, i.e. Alzheimer’s Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson’s Disease, or Cerebrovascular Disease were included in the study. NPS were assessed using the Neuropsychiatric Inventory – Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter atrophy. Results: Although NPS were frequent across the five disease groups, participants with Frontotemporal Dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both Frontotemporal Dementia and Parkinson’s Disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities. Conclusions: In participants with neurodegenerative and cerebrovascular diseases, our results suggest that increased cortical atrophy and white matter hyperintensities burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.

If the tendency to discount rewards reflects individuals' general level of impulsiveness, then the discounting of delayed and probabilistic rewards should be negatively correlated: The less a person is able to wait for delayed rewards, the more they should take chances on receiving probabilistic rewards. It has been suggested that damage to the ventromedial prefrontal cortex (vmPFC) increases individuals' impulsiveness, but both intertemporal choice and risky choice have only recently been assayed in the same patients with vmPFC damage. Here, we assess both delay and probability discounting in individuals with vmPFC damage (n = 8) or with medial temporal lobe (MTL) damage (n = 10), and in age- and education-matched controls (n = 30). On average, MTL-lesioned individuals discounted delayed rewards at normal rates but discounted probabilistic rewards more shallowly than controls. In contrast, vmPFC-lesioned individuals discounted delayed rewards more steeply but probabilistic rewards more shallowly than controls. These results suggest that vmPFC lesions affect the weighting of reward amount relative to delay and certainty in opposite ways. Moreover, whereas MTL-lesioned individuals and controls showed typical, nonsignificant correlations between the discounting of delayed and probabilistic rewards, vmPFC-lesioned individuals showed a significant negative correlation, as would be expected if vmPFC damage increases impulsiveness more in some patients than in others. Although these results are consistent with the hypothesis that vmPFC plays a role in impulsiveness, it is unclear how they could be explained by a single mechanism governing valuation of both delayed and probabilistic rewards.

Successful segmentation of the total intracranial vault (ICV) and ventricles is of critical importance when studying neurodegeneration through neuroimaging. We present iCVMapper and VentMapper, robust algorithms that use a convolutional neural network (CNN) to segment the ICV and ventricles from both single and multi-contrast MRI data. Our models were trained on a large dataset from two multi-site studies (N=528 subjects for ICV, N=501 for ventricular segmentation) consisting of older adults with varying degrees of cerebrovascular lesions and atrophy, which pose significant challenges for most segmentation approaches. The models were tested on 238 participants, including subjects with vascular cognitive impairment and high white matter hyperintensity burden. Two of the three test sets came from studies not used in the training dataset. We assessed our algorithms relative to four state-of-the-art ICV extraction methods (MONSTR, BET, Deep Extraction, FreeSurfer), as well as a ventricular segmentation tool (FreeSurfer). Our multi-contrast models outperformed other methods across all evaluation metrics, with average Dice coefficients of 0.98 and 0.94 for ICV and ventricular segmentation respectively. Both models were also the most time efficient, segmenting the structures in orders of magnitude faster than some of the other available methods. Our networks showed an increased accuracy with the use of a conditional random field (CRF) as a post-processing step. We further validated both segmentation models, highlighting their robustness to images with lower resolution and signal-to-noise ratio, compared to tested techniques. The pipeline and models are available at: https://icvmapp3r.readthedocs.io and https://ventmapp3r.readthedocs.io to enable further investigation of the roles of ICV and ventricles in relation to normal aging and neurodegeneration in large multi-site studies.

Objectives: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit's Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders?. Methods/Design: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer's disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson's disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery. Results: We found three components in the ZBI. The first was “overall burden” and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = −0.566, basic ADLs r = −0.43), (2) moderately related to cognition (MoCA r = −0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners. Conclusions: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions.

Background:Vascular cognitive impairment (VCI) post-stroke is frequent but may go undetected, which highlights the need to better screen cognitive functioning following a stroke.Aim:We examined the clinical utility of the Montreal Cognitive Assessment (MoCA) in detecting cognitive impairment against a gold-standard neuropsychological battery.Methods:We assessed cognitive status with a comprehensive battery of neuropsychological tests in 161 individuals who were at least 3-months post-stroke. We used receiver operating characteristic (ROC) curves to identify two cut points for the MoCA to maximize sensitivity and specificity at a minimum 90% threshold. We examined the utility of the Symbol Digit Modalities Test, a processing speed measure, to determine whether this additional metric would improve classification relative to the MoCA total score alone.Results:Using two cut points, 27% of participants scored ≤ 23 and were classified as high probability of cognitive impairment (sensitivity 92%), and 24% of participants scored ≥ 28 and were classified as low probability of cognitive impairment (specificity 91%). The remaining 48% of participants scored from 24 to 27 and were classified as indeterminate probability of cognitive impairment. The addition of a processing speed measure improved classification for the indeterminate group by correctly identifying 65% of these individuals, for an overall classification accuracy of 79%.Conclusions:The utility of the MoCA in detecting cognitive impairment post-stroke is improved when using a three-category approach. The addition of a processing speed measure provides a practical and efficient method to increase confidence in the determined outcome while minimally extending the screening routine for VCI.

White matter hyperintensities (WMHs) are frequently observed on structural neuroimaging of elderly populations and are associated with cognitive decline and increased risk of dementia. Many existing WMH segmentation algorithms produce suboptimal results in populations with vascular lesions or brain atrophy, or require parameter tuning and are computationally expensive. Additionally, most algorithms do not generate a confidence estimate of segmentation quality, limiting their interpretation. MRI-based segmentation methods are often sensitive to acquisition protocols, scanners, noise-level, and image contrast, failing to generalize to other populations and out-of-distribution datasets. Given these concerns, we propose a novel Bayesian 3D convolutional neural network with a U-Net architecture that automatically segments WMH, provides uncertainty estimates of the segmentation output for quality control, and is robust to changes in acquisition protocols. We also provide a second model to differentiate deep and periventricular WMH. Four hundred thirty-two subjects were recruited to train the CNNs from four multisite imaging studies. A separate test set of 158 subjects was used for evaluation, including an unseen multisite study. We compared our model to two established state-of-the-art techniques (BIANCA and DeepMedic), highlighting its accuracy and efficiency. Our Bayesian 3D U-Net achieved the highest Dice similarity coefficient of 0.89 ± 0.08 and the lowest modified Hausdorff distance of 2.98 ± 4.40 mm. We further validated our models highlighting their robustness on "clinical adversarial cases" simulating data with low signal-to-noise ratio, low resolution, and different contrast (stemming from MRI sequences with different parameters). Our pipeline and models are available at: https://hypermapp3r.readthedocs.io.

Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson’s disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in PARK2 in the FTD cohort, and in NOTCH3 in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.

ObjectiveTo assess overlap and uniqueness of established behavioral markers of speed of processing for different aspects of visual information within a cerebrovascular disease cohort, and to examine the link between these speed of processing markers and functional behavior, specifically walking.MethodsA cohort of 161 participants with cerebrovascular disease recruited to the Ontario Neurodegenerative Disease Research Initiative (ONDRI) were examined with three types of assessments: neuropsychology, saccadic eye movement and gait. Principal component analysis (PCA) and canonical correlation analysis (CCA) were performed on select variables from these assessments to reveal commonalities and discrepancies among the measures.ResultsPCA analysis revealed different variable patterns between neuropsychology and saccade assessments, with the first component characterized primarily by neuropsychology, and the second and third components more influenced by the saccade assessments. CCA analysis did not reveal association between different types of assessments with the exception of a modest, but significant, positive association between speed of processing measures from the neuropsychological assessments and gait speed.DiscussionNeuropsychological tests and the pro-saccade task can be used for assessment of speed of processing for two major features of visual information, visual perception vs. spatial location. Despite a general lack of association between different types of assessments, combining gait speed as an important contributor to the models reinforces the idea of the link between speed of processing and complex function such as walking, and provides support for the importance of attending to the potential consequences of changes in speed of processing after neurologic injury.

White matter hyperintensities (WMH) are frequently observed on structural neuroimaging of elderly populations and are associated with cognitive decline and increased risk of dementia. Many existing WMH segmentation algorithms produce suboptimal results in populations with vascular lesions or brain atrophy, or require parameter tuning and are computationally expensive. Additionally, most algorithms do not generate a confidence estimate of segmentation quality, limiting their interpretation. MRI-based segmentation methods are often sensitive to acquisition protocols, scanners, noise-level, and image contrast, failing to generalize to other populations and out-of-distribution datasets. Given these concerns, we propose a novel Bayesian 3D Convolutional Neural Network (CNN) with a U-Net architecture that automatically segments WMH, provides uncertainty estimates of the segmentation output for quality control and is robust to changes in acquisition protocols. We also provide a second model to differentiate deep and periventricular WMH. 432 subjects were recruited to train the CNNs from four multi-site imaging studies. A separate test set of 158 subjects was used for evaluation, including an unseen multi-site study. We compared our model to two established state-of-the-art techniques (BIANCA and DeepMedic), highlighting its accuracy and efficiency. Our Bayesian 3D U-Net achieved the highest Dice similarity coefficient of 0.89 ± 0.08 and the lowest modified Hausdorff distance of 2.98 ± 4.40 mm. We further validated our models highlighting their robustness on ‘clinical adversarial cases’ simulating data with low signal-to-noise ratio, low resolution, and different contrast (stemming from MRI sequences with different parameters). Our pipeline and models are available at: https://hypermapp3r.readthedocs.io

Introduction: Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases.Methods: 513 participants with Alzheimer’s Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia (FTD), Parkinson’s Disease, or Cerebrovascular Disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness.Results: A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex(female), global cognition, and right parietal and occipital WMH.Conclusions: Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases.

Intertemporal choices require trade-offs between short-term and long-term outcomes. Ventromedial prefrontal cortex (vmPFC) damage causes steep discounting of future rewards (delay discounting; DD) and impoverished episodic future thinking (EFT). The role of vmPFC in reward valuation, EFT, and their interaction during intertemporal choice is still unclear. Here, twelve patients with lesions to vmPFC and forty-one healthy controls chose between smaller-immediate and larger-delayed hypothetical monetary rewards while we manipulated reward magnitude and the availability of EFT cues. In the EFT condition, participants imagined personal events to occur at the delays associated with the larger-delayed rewards. We found that DD was steeper in vmPFC patients compared to controls, and not modulated by reward magnitude. However, EFT cues downregulated DD in vmPFC patients as well as controls. These findings indicate that vmPFC integrity is critical for the valuation of (future) rewards, but not to instill EFT in intertemporal choice.

Objectives Recent studies suggest that interindividual genetic differences in glial-dependent CSF flow through the brain parenchyma, known as glymphatic flow, may trigger compensatory changes in human sleep physiology. In animal models, brain perivascular spaces are a critical conduit for glymphatic flow. We tested the hypothesis that MRI-visible PVS volumes, a putative marker of perivascular dysfunction, are associated with compensatory differences in real-world human sleep behavior. Methods We analyzed data from 152 cerebrovascular disease patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). PVS volumes were measured using 3T-MRI. Self-reported total sleep time, time in bed, and daytime dysfunction were extracted from the Pittsburgh Sleep Quality Index. Results Individuals with greater PVS volumes reported longer time in bed (+0.85 h per log10 proportion of intracranial volume (ICV) occupied by PVS, SE = 0.30, p = 0.006) and longer total sleep times (+0.70 h per log10 proportion of ICV occupied by PVS volume, SE = 0.33, p = 0.04), independent of vascular risk factors, sleep apnea, nocturnal sleep disturbance, depression, and global cognitive status. Further analyses suggested that the positive association between PVS volumes and total sleep time was mediated by greater time in bed. Moreover, despite having on average greater total sleep times, individuals with greater basal ganglia PVS volumes were more likely to report daytime dysfunction (OR 5.63 per log10 proportion of ICV occupied by PVS, 95% CI: 1.38–22.26, p = 0.018). Conclusions Individuals with greater PVS volumes spend more time in bed, resulting in greater total sleep time, which may represent a behavioral compensatory response to perivascular space dysfunction.

Purpose: Dementia due to cerebrovascular disease (CVD) is common. Detecting early cognitive decline in CVD is critical because addressing risk factors may slow or prevent dementia. This study used a multidomain discourse analysis approach to determine the spoken language signature of CVD-related cognitive impairment. Method: Spoken language and neuropsychological assessment data were collected prospectively from 157 participants with CVD as part of the Ontario Neurodegenerative Disease Research Initiative, a longitudinal, observational study of neurodegenerative disease. Participants were categorized as impaired (n = 92) or cognitively normal for age (n = 65) based on neuropsychology criteria. Spoken language samples were transcribed orthographically and annotated for 13 discourse features, across five domains. Discriminant function analyses were used to determine a minimum set of discourse variables, and their estimated weights, for maximizing diagnostic group separation. Results: The optimal discriminant function that included 10 of 13 discourse measures correctly classified 78.3% of original cases (69.4% cross-validated cases) with a sensitivity of 77.2% and specificity of 80.0%. Conclusion: Spoken discourse appears to be a sensitive measure for detecting cognitive impairment in CVD with measures of productivity, information content, and information efficiency heavily weighted in the final algorithm.

BackgroundRegional changes to cortical thickness in individuals with neurodegenerative and cerebrovascular diseases can be estimated using specialised neuroimaging software. However, the presence of cerebral small vessel disease, focal atrophy, and cortico-subcortical stroke lesions, pose significant challenges that increase the likelihood of misclassification errors and segmentation failures.PurposeThe main goal of this study was to examine a correction procedure developed for enhancing FreeSurfer’s cortical thickness estimation tool, particularly when applied to the most challenging MRI obtained from participants with chronic stroke and cerebrovascular disease, with varying degrees of neurovascular lesions and brain atrophy.MethodsIn 155 cerebrovascular disease patients enrolled in the Ontario Neurodegenerative Disease Research Initiative (ONDRI), FreeSurfer outputs were compared between a fully automated, unmodified procedure and a corrected procedure that accounted for potential sources of error due to atrophy and neurovascular lesions. Quality control (QC) measures were obtained from both procedures. Association between cortical thickness and global cognitive status as assessed by the Montreal Cognitive Assessment (MoCA) score was also investigated from both procedures.ResultsCorrected procedures increased ‘Acceptable’ QC ratings from 18% to 76% for the cortical ribbon and from 38% to 92% for tissue segmentation. Corrected procedures reduced ‘Fail’ ratings from 11% to 0% for the cortical ribbon and 62% to 8% for tissue segmentation. FreeSurfer-based segmentation of T1-weighted white matter hypointensities were significantly greater in the corrected procedure (5.8mL vs. 15.9mL, pConclusionsThese findings suggest that correction procedures that account for brain atrophy and neurovascular lesions can significantly improve FreeSurfer’s segmentation results, reduce failure rates, and potentially increase sensitivity to examine brain-behaviour relationships. Future work will examine relationships between cortical thickness, cerebral small vessel disease, and neurodegenerative disease in the ONDRI study.

ObjectiveIn individuals over the age of 65, concomitant neurodegenerative pathologies contribute to cognitive and/or motor decline and can be aggravated by cerebrovascular disease, but our understanding of how these pathologies synergize to produce the decline represents an important knowledge gap. The Ontario Neurodegenerative Disease Research Initiative (ONDRI), a multi-site, longitudinal, observational cohort study, recruited participants across multiple prevalent neurodegenerative diseases and cerebrovascular disease, collecting a wide array of data and thus allowing for deep investigation into common and unique phenotypes. This paper describes baseline features of the ONDRI cohort, understanding of which is essential when conducting analyses or interpreting results.MethodsFive disease cohorts were recruited: Alzheimer’s disease/amnestic mild cognitive impairment (AD/MCI), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson’s disease (PD), and cerebrovascular disease (CVD). Assessment platforms included clinical, neuropsychology, eye tracking, gait and balance, neuroimaging, retinal imaging, genomics, and pathology. We describe recruitment, data collection, and data curation protocols, and provide a summary of ONDRI baseline characteristics.Results520 participants were enrolled. Most participants were in the early stages of disease progression. Participants had a median age of 69 years, a median Montreal Cognitive Assessment score of 25, a median percent of independence of 100 for basic activities of daily living, and a median of 93 for instrumental activities. Variation between disease cohorts existed for age, level of cognition, and geographic location.ConclusionONDRI data will enable exploration into unique and shared pathological mechanisms contributing to cognitive and motor decline across the spectrum of neurodegenerative diseases.

Remembering and imagining specific, personal experiences can help shape our decisions. For example, cues to imagine future events can reduce delay discounting (i.e., increase the subjective value of future rewards). It is not known, however, whether such cues can also modulate other forms of reward discounting, such as probability discounting (i.e., the decrease in the subjective value of a possible reward as the odds against its occurrence increase). In addition, it is unclear whether there are age-related differences in the effects of cueing on either delay or probability discounting. Accordingly, young and older adult participants were administered delay and probability discounting tasks both with and without cues to imagine specific, personally meaningful events. As expected, cued episodic imagining decreased the discounting of delayed rewards. Notably, however, this effect was significantly less pronounced in older adults. In contrast to the effects of cueing on delay discounting, personally relevant event cues had little or no effect on the discounting of probabilistic rewards in either young or older adults; Bayesian analysis revealed compelling support for the null hypothesis that event cues do not modulate the subjective value of probabilistic rewards. In sum, imagining future events appears only to affect decisions involving delayed rewards. Although the cueing effect is smaller in older adults, nevertheless, it likely contributes to how adults of all ages evaluate delayed rewards and thus, it is, in fact, about time.

Fisheries bycatch is a widespread and serious issue that leads to declines of many important and threatened marine species. However, documenting the distribution, abundance, population trends and threats to sparse populations of marine species is often beyond the capacity of developing countries because such work is complex, time consuming and often extremely expensive. We have developed a flexible tool to document spatial distribution and population trends for dugongs and other marine species in the form of an interview questionnaire supported by a structured data upload sheet and a comprehensive project manual. Recognising the effort invested in getting interviewers to remote locations, the questionnaire is comprehensive, but low cost. The questionnaire has already been deployed in 18 countries across the Indo-Pacific region. Project teams spent an average of USD 5,000 per country and obtained large data sets on dugong distribution, trends, catch and bycatch, and threat overlaps. Findings indicated that >50% of respondents had never seen dugongs and that 20% had seen a single dugong in their lifetimes despite living and fishing in areas of known or suspected dugong habitat, suggesting that dugongs occurred in low numbers. Only 3% of respondents had seen mother and calf pairs, indicative of low reproductive output. Dugong hunting was still common in several countries. Gillnets and hook and line were the most common fishing gears, with the greatest mortality caused by gillnets. The questionnaire has also been used to study manatees in the Caribbean, coastal cetaceans along the eastern Gulf of Thailand and western Peninsular Malaysia, and river dolphins in Peru. This questionnaire is a powerful tool for studying distribution and relative abundance for marine species and fishery pressures, and determining potential conservation hotspot areas. We provide the questionnaire and supporting documents for open-access use by the scientific and conservation communities.

The capacity to anticipate future experiences of regret has been hypothesized to explain otherwise irrational aspects of human decision-making, including the certainty effect (Kahneman and Tversky (1979) Econometrica 47:263–291) and the common ratio effect (Allais (1953) Econometrica 21:503–546). The anticipated regret hypothesis predicts that individuals incapable of episodically imagining their personal futures, as has been reported for people with extensive damage to medial temporal lobe structures and resulting deficits in episodic thought, should be immune to these effects. We report that K.C., who has extensive bilateral damage to his hippocampus and adjacent medial temporal lobe structures and nearly complete deficits in his ability to episodically imagine his personal future, nonetheless displays both the certainty and the common ratio effects. These results suggest that the episodic anticipation of future regret does not explain the general human tendency to display the certainty and common ratio effects. © 2014 Wiley Periodicals, Inc.

Corneal avascularity—the absence of blood vessels in the cornea—is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders1-4. But the molecular underpinnings of the avascular phenotype have until now remained obscure5-10 and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap11 by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/− mice12,13 and Pax6+/− patients with aniridia14 are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6+/− mice. Manatees, the only known creatures uniformly to have vascularized corneas15, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea.

Deficits in episodic memory are associated with deficits in the ability to imagine future experiences (i.e., mental time travel). We show that K.C., a person with episodic amnesia and an inability to imagine future experiences, nonetheless systematically discounts the value of future rewards, and his discounting is within the range of controls in terms of both rate and consistency. Because K.C. is neither able to imagine personal uses for the rewards nor provide a rationale for selecting larger future rewards over smaller current rewards, the current study demonstrates a dissociation between imagining and making decisions involving the future. Thus, although those capable of mental time travel may use it in making decisions about future rewards, the present results demonstrate that it is not required for such decisions.

As an initial step toward developing a theory of visual concealment, we assessed whether people would use factors known to influence visual search difficulty when the degree of concealment of objects among distractors was varied. In Experiment 1, participants arranged search objects (shapes, emotional faces, and graphemes) to create displays in which the targets were in plain sight but were either easy or hard to find. Analyses of easy and hard displays created during Experiment 1 revealed that the participants reliably used factors known to influence search difficulty (e.g., eccentricity, target—distractor similarity, presence/absence of a feature) to vary the difficulty of search across displays. In Experiment 2, a new participant group searched for the targets in the displays created by the participants in Experiment 1. Results indicated that search was more difficult in the hard than in the easy condition. In Experiments 3 and 4, participants used presence versus absence of a feature to vary search difficulty with several novel stimulus sets. Taken together, the results reveal a close link between the factors that govern concealment and the factors known to influence search difficulty, suggesting that a visual search theory can be extended to form the basis of a theory of visual concealment.

We report a case study of an individual (TE) for whom inanimate objects, such as letters, numbers, simple shapes, and even furniture, are experienced as having rich and detailed personalities. TE reports that her object-personality pairings are stable over time, occur independent of her intentions, and have been there for as long as she can remember. In these respects, her experiences are indicative of synesthesia. Here we show that TE's object-personality pairings are very consistent across test-retest, even for novel objects. A qualitative analysis of TE's personality descriptions revealed that her personifications are extremely detailed and multi-dimensional, and that her personifications of familiar and novel objects differ in specific ways. We also found that TE's eye movements can be biased by the emotional associations she has with letters and numbers. These findings demonstrate that synesthesia can involve complex semantic personifications, which can influence visual attention. Finally, we propose a neural model of normal personification and the unusual personifications that accompany object-personality synesthesia.

Industrialized nations have been successful in reducing incidences of iron deficiency through utilization of multifaceted strategies that build on the capabilities of successful alliances between the public and private sectors. In comparison to developing nations, which have an estimated prevalence of iron deficiency of approximately 40%, the prevalence in industrialized countries is approximately 5%. Such low rates were achieved by various initiatives including widespread availability of affordable iron-fortified foods and implementation of national, science-based programs. Despite these successes, however, iron deficiency remains a critical problem among certain subpopulations (e.g., people of low socioeconomic status or recent immigrants who do not consume iron-fortified foods). Strengthening alliances among the private and public sectors and academia in communications efforts about iron deficiency and promoting iron-rich foods as well as iron-fortified foods is necessary to reduce iron deficiency in these populations.