Transcranial magnetic stimulation to the angular gyrus modulates the temporal dynamics of the hippocampus and entorhinal cortex.

Transcranial magnetic stimulation (TMS) delivered to the angular gyrus (AG) affects hippocampal function and associated behaviors (Thakral PP, Madore KP, Kalinowski SE, Schacter DL. Modulation of hippocampal brain networks produces changes in episodic simulation and divergent thinking. 2020a. Proc Natl Acad Sci U S A. 117:12729-12740). Here, we examine if functional magnetic resonance imaging (fMRI)-guided TMS disrupts the gradient organization of temporal signal properties, known as the temporal organization, in the hippocampus (HPC) and entorhinal cortex (ERC). For each of 2 TMS sessions, TMS was applied to either a control site (vertex) or to a left AG target region (N = 18; 14 females). Behavioral measures were then administered, and resting-state scans were acquired. Temporal dynamics were measured by tracking change in the fMRI signal (i) "within" single voxels over time, termed single-voxel autocorrelation and (ii) "between" different voxels over time, termed intervoxel similarity. TMS reduced AG connectivity with the hippocampal target and induced more rapid shifting of activity in single voxels between successive time points, lowering the single-voxel autocorrelation, within the left anteromedial HPC and posteromedial ERC. Intervoxel similarity was only marginally affected by TMS. Our findings suggest that hippocampal-targeted TMS disrupts the functional properties of the target site along the anterior/posterior axis. Further studies should examine the consequences of altering the temporal dynamics of these medial temporal areas to the successful processing of episodic information under task demand.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Connectivity between default mode and frontoparietal networks mediates the association between global amyloid-ß and episodic memory.

Βeta-amyloid (Aß) is a neurotoxic protein that deposits early in the pathogenesis of preclinical Alzheimer's disease. We aimed to identify network connectivity that may alter the negative effect of Aß on cognition. Following assessment of memory performance, resting-state fMRI, and mean cortical PET-Aß, a total of 364 older adults (286 with clinical dementia rating [CDR-0], 59 with CDR-0.5 and 19 with CDR-1, mean age: 74.0 ± 6.4 years) from the OASIS-3 sample were included in the analysis. Across all participants, a partial least squares regression showed that lower connectivity between posterior medial default mode and frontoparietal networks, higher within-default mode, and higher visual-motor connectivity predict better episodic memory. These connectivities partially mediate the effect of Aß on episodic memory. These results suggest that connectivity strength between the precuneus cortex and the superior frontal gyri may alter the negative effect of Aß on episodic memory. In contrast, education was associated with different functional connectivity patterns. In conclusion, functional characteristics of specific brain networks may help identify amyloid-positive individuals with a higher likelihood of memory decline, with implications for AD clinical trials.

Toward personalized cognitive diagnostics of at-genetic-risk Alzheimer's disease.

Spatial navigation is emerging as a critical factor in identifying preclinical Alzheimer's disease (AD). However, the impact of interindividual navigation ability and demographic risk factors (e.g., APOE, age, and sex) on spatial navigation make it difficult to identify persons "at high risk" of AD in the preclinical stages. In the current study, we use spatial navigation big data (n = 27,108) from the Sea Hero Quest (SHQ) game to overcome these challenges by investigating whether big data can be used to benchmark a highly phenotyped healthy aging laboratory cohort into high- vs. low-risk persons based on their genetic (APOE) and demographic (sex, age, and educational attainment) risk factors. Our results replicate previous findings in APOE ε4 carriers, indicative of grid cell coding errors in the entorhinal cortex, the initial brain region affected by AD pathophysiology. We also show that although baseline navigation ability differs between men and women, sex does not interact with the APOE genotype to influence the manifestation of AD-related spatial disturbance. Most importantly, we demonstrate that such high-risk preclinical cases can be reliably distinguished from low-risk participants using big-data spatial navigation benchmarks. By contrast, participants were undistinguishable on neuropsychological episodic memory tests. Taken together, we present evidence to suggest that, in the future, SHQ normative benchmark data can be used to more accurately classify spatial impairments in at-high-risk of AD healthy participants at a more individual level, therefore providing the steppingstone for individualized diagnostics and outcome measures of cognitive symptoms in preclinical AD.

Sex differences in histopathological markers of cerebral amyloid angiopathy and related hemorrhage.

BACKGROUND: Men with cerebral amyloid angiopathy (CAA) may have an earlier onset of intracerebral hemorrhage and a more hemorrhagic disease course compared to women. In this cohort study, we investigated sex differences in histopathological markers associated with amyloid-ß burden and hemorrhage in cognitively impaired individuals and patients with CAA, using neuropathological data from two autopsy databases. METHODS: First, we investigated presence of parenchymal (Thal score) and vascular amyloid-ß (CAA severity score) in cognitively impaired individuals from the National Alzheimer's Coordinating Center (NACC) neuropathology database. Next, we examined sex differences in hemorrhagic ex vivo magnetic resonance imaging (MRI) markers and local cortical iron burden and the interaction of sex on factors associated with cortical iron burden (CAA percentage area and vessel remodeling) in patients with pathologically confirmed clinical CAA from the Massachusetts General Hospital (MGH) CAA neuropathology database. RESULTS: In 6120 individuals from the NACC database (45% women, mean age 80 years), the presence of parenchymal amyloid-ß (odds ratio (OR) (95% confidence interval (CI)) =0.68 (0.53-0.88)) but not vascular amyloid-ß was less in men compared to women. In 19 patients with definite CAA from the MGH CAA database (35% women, mean age 75 years), a lower microbleed count (p < 0.001) but a higher proportion of cortical superficial siderosis and a higher local cortical iron burden was found in men (p < 0.001) compared to women. CAA percentage area was comparable in men and women (p = 0.732). Exploratory analyses demonstrated a possible stronger negative relation between cortical CAA percentage area and cortical iron density in men compared to women (p = 0.03). CONCLUSION: Previously observed sex differences in hemorrhage onset and progression in CAA patients are likely not due to differences in global CAA severity between men and women. Other factors, such as vascular remodeling, may contribute, but future studies are necessary to replicate our findings in larger data sets and to further investigate the underlying mechanisms behind these complex sex differences.

Genetic influences on brain and cognitive health and their interactions with cardiovascular conditions and depression.

Approximately 40% of dementia cases could be prevented or delayed by modifiable risk factors related to lifestyle and environment. These risk factors, such as depression and vascular disease, do not affect all individuals in the same way, likely due to inter-individual differences in genetics. However, the precise nature of how genetic risk profiles interact with modifiable risk factors to affect brain health is poorly understood. Here we combine multiple data resources, including genotyping and postmortem gene expression, to map the genetic landscape of brain structure and identify 367 loci associated with cortical thickness and 13 loci associated with white matter hyperintensities (P < 5×10-8), with several loci also showing a significant association with cognitive function. We show that among 220 unique genetic loci associated with cortical thickness in our genome-wide association studies (GWAS), 95 also showed evidence of interaction with depression or cardiovascular conditions. Polygenic risk scores based on our GWAS of inferior frontal thickness also interacted with hypertension in predicting executive function in the Canadian Longitudinal Study on Aging. These findings advance our understanding of the genetic underpinning of brain structure and show that genetic risk for brain and cognitive health is in part moderated by treatable mid-life factors.

Associations Between Age at Menopause, Vascular Risk, and 3-Year Cognitive Change in the Canadian Longitudinal Study on Aging.

BACKGROUND AND OBJECTIVES: Mounting evidence supports sex differences in Alzheimer disease (AD) risk. Vascular and hormonal factors may together contribute to AD risk in female adults. We investigated whether age at menopause, vascular risk, and history of hormone therapy (HT) containing estrogens together influence cognition over a 3-year follow-up period. We hypothesized that earlier menopause and elevated vascular risk would have a synergistic association with lower cognitive scores at follow-up and that HT containing estrogens would attenuate this synergistic association to preserve cognition. METHODS: We used data from postmenopausal female participants and age-matched male participants in the Canadian Longitudinal Study on Aging. Vascular risk was calculated using a summary score of elevated blood pressure, antihypertensive medications, elevated low-density lipoprotein cholesterol, diabetes, smoking, and obesity. Cognition was measured with a global cognitive composite at baseline and 3-year follow-up. Linear models tested independent and interactive associations of age at menopause, vascular risk, and HT history with cognition at 3-year follow-up, adjusting for baseline cognition, baseline age, years of education, and test language (English/French). RESULTS: We included 8,360 postmenopausal female participants (mean age at baseline = 65.0 ± 8.53 years, mean age at menopause = 50.1 ± 4.62 years) and 8,360 age-matched male participants for comparison. There was an interaction between age at menopause and vascular risk, such that earlier menopause and higher vascular risk were synergistically associated with lower cognitive scores at follow-up (ß = 0.013, 95% CI 0.001-0.025, p = 0.03). In stratified analyses, vascular risk was associated with lower cognitive scores in female participants with earlier menopause (menopausal ages 35-48 years; ß = -0.044, 95% CI -0.066 to -0.022, p < 0.001), but not average (ages 49-52 years; ß = -0.007, 95% CI -0.027 to 0.012, p = 0.46) or later menopause (ages 53-65 years; ß = 0.003, 95% CI -0.020 to 0.025, p = 0.82). The negative association of vascular risk with cognition in female participants with earlier menopause was stronger than the equivalent association in age-matched male participants. HT history did not further modify the synergistic association of age at menopause and vascular risk with follow-up cognition (ß = -0.005, 95% CI -0.032 to 0.021, p = 0.69). DISCUSSION: Endocrine and vascular processes may synergistically contribute to increased risk of cognitive decline in female adults. These findings have implications for the development of sex-specific dementia prevention strategies.

Vascular contributions to cognitive decline: Beyond amyloid and tau in the Harvard Aging Brain Study.

In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk. We used exploratory factor analysis to extract orthogonal factors from these variables and their interactions. These factors were used in a regression model to explain longitudinal Preclinical Alzheimer Cognitive Composite-5 (PACC) decline (follow-up = 8.5 ±2.7 years). We next examined whether gray matter volume atrophy acts as a mediator of factors and PACC decline. Latent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow independently explain cognitive decline beyond amyloid and tau. Gray matter volume atrophy mediates these associations with the strongest effect on white matter injury. These results suggest that systemic vascular risk contributes to cognitive decline beyond current markers of cerebrovascular injury, amyloid, and tau.

Identifying longitudinal cognitive resilience from cross-sectional amyloid, tau, and neurodegeneration.

BACKGROUND: Leveraging Alzheimer's disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR. METHODS: We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aß, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women). RESULTS: The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline. CONCLUSION: These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity.

Rethinking the residual approach: Leveraging machine learning to operationalize cognitive resilience in Alzheimer's disease.

Cognitive resilience describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. We propose an alternative strategy which overcomes the standard approach's limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and construct to be measured and achieves better estimation accuracy on simulated ground-truth data.

Vestibular contribution to path integration deficits in 'at-genetic-risk' for Alzheimer's disease.

Path integration changes may precede a clinical presentation of Alzheimer's disease by several years. Studies to date have focused on how spatial cell changes affect path integration in preclinical AD. However, vestibular input is also critical for intact path integration. Here, we developed the vestibular rotation task that requires individuals to manually point an iPad device in the direction of their starting point following rotational movement, without any visual cues. Vestibular features were derived from the sensor data using feature selection. Machine learning models illustrate that the vestibular features accurately classified Apolipoprotein E ε3ε4 carriers and ε3ε3 carrier controls (mean age 62.7 years), with 65% to 79% accuracy depending on task trial. All machine learning models produced a similar classification accuracy. Our results demonstrate the cross-sectional role of the vestibular system in Alzheimer's disease risk carriers. Future investigations should examine if vestibular functions explain individual phenotypic heterogeneity in path integration among Alzheimer's disease risk carriers.

Spatial orientation - a stable marker for vascular cognitive impairment?

Vascular cognitive impairment (VCI) is the second most prevalent form of dementia, but little is known about the early cognitive and neuroimaging markers. Spatial navigation deficits are an emerging marker for Alzheimer's disease (AD), yet less is known about spatial orientation deficits sensitive to VCI. This case report follows up on the first VCI patient identified to have an egocentric orientation deficit. The study aimed to examine the patient's spatial deficits three years on and gain insights from the addition of the patient's MRI brain scan. A battery of spatial navigation tasks were administered following neuropsychological assessment. Results continue to show spatial orientation deficits. Critically, these changes appear stable and are sensitive to novel spatial tests. Whereas conventional screening tools demonstrate patient recovery. MRI DTI analysis indicates a non-significant trend towards loss of structural integrity to the posterior tracts of the longitudinal superior fasciculus (SLF), while the medial temporal lobe, typically implicated in spatial navigation, is unaffected. This finding potentially reflects reduced network connectivity in posterior to anterior white matter tracts co-existing with spatial orientation deficits. Findings have clinical utility and show spatial orientation as a potential sensitive cognitive marker for VCI.

Spatial cognition is associated with levels of phosphorylated-tau and ß-amyloid in clinically normal older adults.

Spatial cognition is associated with Alzheimer's disease (AD) biomarkers in the symptomatic stages of the disease. We investigated whether cerebrospinal fluid (CSF) biomarkers (phosphorylated-tau [p-tau] and ß-amyloid) are associated with poorer spatial cognition in clinically normal older adults. Participants were 1875 clinically normal adults (age 67.8 [8.5] years) from the European Prevention of Alzheimer's Dementia Consortium. Mixed effect models assessed the cross-sectional association between p-tau181, ß-amyloid1-42 (Aß1-42) and p-tau181/Aß1-42 ratio and spatial cognition measured using semi-automated Supermarket Task and the 4 Mountains Task. Levels of p-tau181, Aß1-42, and p-tau181/Aß1-42 ratio were significantly associated with spatial cognition scores on both tasks. The p-tau181/Aß1-42 ratio showed the largest effect sizes (ß = -0.04/0.05, p < 0.001). Lower entorhinal cortical volume was associated with poorer outcomes on both tasks (ß = 0.06, p < 0.002) and accounted for 18%-22% of the direct association between p-tau181 and spatial cognition scores. In conclusion, degeneration of the entorhinal cortex mediates a significant proportion of the association between p-tau181 and spatial assessments in cognitively normal adults. Future studies should focus on increasing the sensitivity of digital spatial assessments.

Medial temporal lobe structure, mnemonic and perceptual discrimination in healthy older adults and those at risk for mild cognitive impairment.

Cognitive tests sensitive to the integrity of the medial temporal lobe (MTL), such as mnemonic discrimination of perceptually similar stimuli, may be useful early markers of risk for cognitive decline in older populations. Perceptual discrimination of stimuli with overlapping features also relies on MTL but remains relatively unexplored in this context. We assessed mnemonic discrimination in two test formats (Forced Choice, Yes/No) and perceptual discrimination of objects and scenes in 111 community-dwelling older adults at different risk status for cognitive impairment based on neuropsychological screening. We also investigated associations between performance and MTL sub-region volume and thickness. The at-risk group exhibited reduced entorhinal thickness and impaired perceptual and mnemonic discrimination. Perceptual discrimination impairment partially explained group differences in mnemonic discrimination and correlated with entorhinal thickness. Executive dysfunction accounted for Yes/No deficits in at-risk adults, demonstrating the importance of test format for the interpretation of memory decline. These results suggest that perceptual discrimination tasks may be useful tools for detecting incipient cognitive impairment related to reduced MTL integrity in nonclinical populations.

Recent contributions to the field of subjective cognitive decline in aging: A literature review.

Subjective cognitive decline (SCD) is defined as self-experienced, persistent concerns of decline in cognitive capacity in the context of normal performance on objective cognitive measures. Although SCD was initially thought to represent the "worried well," these concerns can be linked to subtle brain changes prior to changes in objective cognitive performance and, therefore, in some individuals, SCD may represent the early stages of an underlying neurodegenerative disease process (e.g., Alzheimer's disease). The field of SCD research has expanded rapidly over the years, and this review aims to provide an update on new advances in, and contributions to, the field of SCD in key areas and themes identified by researchers in this field as particularly important and impactful. First, we highlight recent studies examining sociodemographic and genetic risk factors for SCD, including explorations of SCD across racial and ethnic minoritized groups, and examinations of sex and gender considerations. Next, we review new findings on relationships between SCD and in vivo markers of pathophysiology, utilizing neuroimaging and biofluid data, as well as associations between SCD and objective cognitive tests and neuropsychiatric measures. Finally, we summarize recent work on interventions for SCD and areas of future growth in the field of SCD.

Association of Age at Menopause and Hormone Therapy Use With Tau and ß-Amyloid Positron Emission Tomography.

Importance: Postmenopausal females represent around 70% of all individuals with Alzheimer disease. Previous literature shows elevated levels of tau in cognitively unimpaired postmenopausal females compared with age-matched males, particularly in the setting of high ß-amyloid (Aß). The biological mechanisms associated with higher tau deposition in female individuals remain elusive. Objective: To examine the extent to which sex, age at menopause, and hormone therapy (HT) use are associated with regional tau at a given level of Aß, both measured with positron emission tomography (PET). Design, Setting, and Participants: This cross-sectional study included participants enrolled in the Wisconsin Registry for Alzheimer Prevention. Cognitively unimpaired males and females with at least 1 18F-MK-6240 and 11C-Pittsburgh compound B PET scan were analyzed. Data were collected between November 2006 and May 2021. Exposures: Premature menopause (menopause at younger than 40 years), early menopause (menopause at age 40-45 years), and regular menopause (menopause at older than 45 years) and HT user (current/past use) and HT nonuser (no current/past use). Exposures were self-reported. Main Outcomes and Measures: Seven tau PET regions that show sex differences across temporal, parietal, and occipital lobes. Primary analyses examined the interaction of sex, age at menopause or HT, and Aß PET on regional tau PET in a series of linear regressions. Secondary analyses investigated the influence of HT timing in association with age at menopause on regional tau PET. Results: Of 292 cognitively unimpaired individuals, there were 193 females (66.1%) and 99 males (33.9%). The mean (range) age at tau scan was 67 (49-80) years, 52 (19%) had abnormal Aß, and 106 (36.3%) were APOEε4 carriers. There were 98 female HT users (52.2%) (past/current). Female sex (standardized ß = -0.41; 95% CI, -0.97 to -0.32; P < .001), earlier age at menopause (standardized ß = -0.38; 95% CI, -0.14 to -0.09; P < .001), and HT use (standardized ß = 0.31; 95% CI, 0.40-1.20; P = .008) were associated with higher regional tau PET in individuals with elevated Aß compared with male sex, later age at menopause, and HT nonuse. Affected regions included medial and lateral regions of the temporal and occipital lobes. Late initiation of HT (>5 years following age at menopause) was associated with higher tau PET compared with early initiation (ß = 0.49; 95% CI, 0.27-0.43; P = .001). Conclusions and Relevance: In this study, females exhibited higher tau compared with age-matched males, particularly in the setting of elevated Aß. In females, earlier age at menopause and late initiation of HT were associated with increased tau vulnerability especially when neocortical Aß elevated. These observational findings suggest that subgroups of female individuals may be at higher risk of pathological burden.

Unravelling the relationship between amyloid accumulation and brain network function in normal aging and very mild cognitive decline: a longitudinal analysis.

Pathological changes in the brain begin accumulating decades before the appearance of cognitive symptoms in Alzheimer's disease. The deposition of amyloid beta proteins and other neurotoxic changes occur, leading to disruption in functional connections between brain networks. Discrete characterization of the changes that take place in preclinical Alzheimer's disease has the potential to help treatment development by targeting the neuropathological mechanisms to prevent cognitive decline and dementia from occurring entirely. Previous research has focused on the cross-sectional differences in the brains of patients with mild cognitive impairment or Alzheimer's disease and healthy controls or has concentrated on the stages immediately preceding cognitive symptoms. The present study emphasizes the early preclinical phases of neurodegeneration. We use a longitudinal approach to examine the brain changes that take place during the early stages of cognitive decline in the Open Access Series of Imaging Studies-3 data set. Among 1098 participants, 274 passed the inclusion criteria (i.e. had at least two cognitive assessments and two amyloid scans). Over 90% of participants were healthy at baseline. Over 8-10 years, some participants progressed to very mild cognitive impairment (n = 48), while others stayed healthy (n = 226). Participants with cognitive decline show faster amyloid accumulation in the lateral temporal, motor and parts of the lateral prefrontal cortex. These changes in amyloid levels were linked to longitudinal increases in the functional connectivity of select networks, including default mode, frontoparietal and motor components. Our findings advance the understanding of amyloid staging and the corresponding changes in functional organization of large-scale brain networks during the progression of early preclinical Alzheimer's disease.

Using GPS Tracking to Investigate Outdoor Navigation Patterns in Patients With Alzheimer Disease: Cross-sectional Study.

BACKGROUND: Spatial disorientation is one of the earliest and most distressing symptoms seen in patients with Alzheimer disease (AD) and can lead to them getting lost in the community. Although it is a prevalent problem worldwide and is associated with various negative consequences, very little is known about the extent to which outdoor navigation patterns of patients with AD explain why spatial disorientation occurs for them even in familiar surroundings. OBJECTIVE: This study aims to understand the outdoor navigation patterns of patients with AD in different conditions (alone vs accompanied; disoriented vs not disoriented during the study) and investigate whether patients with AD experienced spatial disorientation when navigating through environments with a high outdoor landmark density and complex road network structure (road intersection density, intersection complexity, and orientation entropy). METHODS: We investigated the outdoor navigation patterns of community-dwelling patients with AD (n=15) and age-matched healthy controls (n=18) over a 2-week period using GPS tracking and trajectory mining analytical techniques. Here, for the patients, the occurrence of any spatial disorientation behavior during this tracking period was recorded. We also used a spatial buffer methodology to capture the outdoor landmark density and features of the road network in the environments that the participants visited during the tracking period. RESULTS: The patients with AD had outdoor navigation patterns similar to those of the controls when they were accompanied; however, when they were alone, they had significantly fewer outings per day (total outings: P<.001; day outings: P=.003; night outings: P<.001), lower time spent moving per outing (P=.001), lower total distance covered per outing (P=.009), lower walking distance per outing (P=.02), and lower mean distance from home per outing (P=.004). Our results did not identify any mobility risk factors for spatial disorientation. We also found that the environments visited by patients who experienced disorientation versus those who maintained their orientation during the tracking period did not significantly differ in outdoor landmark density (P=.60) or road network structure (road intersection density: P=.43; intersection complexity: P=.45; orientation entropy: P=.89). CONCLUSIONS: Our findings suggest that when alone, patients with AD restrict the spatial and temporal extent of their outdoor navigation in the community to successfully reduce their perceived risk of spatial disorientation. Implications of this work highlight the importance for future research to identify which of these individuals may be at an actual high risk for spatial disorientation as well as to explore the implementation of health care measures to help maintain a balance between patients' right to safety and autonomy when making outings alone in the community.

Alternative labeling tool: a minimal algorithm for denoising single-subject resting-state fMRI data with ICA-MELODIC.

Subject-level independent component analysis (ICA) is a well-established and widely used approach in denoising of resting-state functional magnetic resonance imaging (fMRI) data. However, approaches such as ICA-FIX and ICA-AROMA require advanced setups and can be computationally intensive. Here, we aim to introduce a user-friendly, computationally lightweight toolbox for labeling independent signal and noise components, termed Alternative Labeling Tool (ALT). ALT uses two features that require manual tuning: proportion of an independent component's spatial map located inside gray matter and positive skew of the power spectrum. ALT is tightly integrated with the commonly used FMRIB's statistical library (FSL). Using the Open Access Series of Imaging Studies (OASIS-3) ageing dataset (n = 275), we found that ALT shows a high degree of inter-rater agreement with manual labeling (over 86% of true positives for both signal and noise components on average). In conclusion, ALT can be extended to small and large-scale datasets when the use of more complex tools such as ICA-FIX is not possible. ALT will thus allow for more widespread adoption of ICA-based denoising of resting-state fMRI data.

A profile of brain reserve in adults at genetic risk of Alzheimer's disease.

INTRODUCTION: The apolipoprotein E (APOE) ε4 allele is the greatest genetic risk factor for Alzheimer's disease (AD). Our aim was to identify the structural brain measures that mitigate the negative effect of APOE ε4 on cognition, which would have implications for AD diagnosis and treatment trial selection. METHODS: A total of 742 older adults (mean age: 70.1 ± 8.7 years) were stratified by APOE status and classified as cognitively normal (CDR 0) or with very mild dementia (CDR 0.5). Regional brain volume and cognitive performance were measured. RESULTS: There were significant interactions between APOE and CDR on the left precuneus and on bilateral superior frontal volumes. These regions were preserved in CDR-0 ε3/ε4 and ε4/ε4 carriers but were reduced in CDR-0.5 ε3/ε4 and ε4/ε4 carriers, compared to their respective ε3/ε3 counterparts. Educational attainment predicted greater brain reserve. DISCUSSION: This pattern of preserved brain structure in cognitively normal ε4 carriers with comprised medial temporal volume is consistent with the theory of brain reserve.