Cross-sectional and Longitudinal Age-related Disintegration in Functional Connectivity: Reference Ability Neural Network Cohort.

Some theories of aging have linked age-related cognitive decline to a reduction in distinctiveness of neural processing. Observed age-related correlation increases among disparate cognitive tasks have supported the dedifferentiation hypothesis. We previously showed cross-sectional evidence for age-related correlation decreases instead, supporting an alternative disintegration hypothesis. In the current study, we extended our previous research to a longitudinal sample. We tested 135 participants (20-80 years) at two time points-baseline and 5-year follow-up-on a battery of 12 in-scanner tests, each tapping one of four reference abilities. We performed between-tasks correlations within domain (convergent) and between domain (discriminant) at both the behavioral and neural level, calculating a single measure of construct validity (convergent - discriminant). Cross-sectionally, behavioral construct validity was significantly different from chance at each time point, but longitudinal change was not significant. Analysis by median age split revealed that older adults showed higher behavioral validity, driven by higher discriminant validity (lower between-tasks correlations). Participant-level neural validity decreased over time, with convergent validity consistently greater than discriminant validity; this finding was also observed at the cross-sectional level. In addition, a disproportionate decrease in neural validity with age remained significant after controlling for demographic factors. Factors predicting longitudinal changes in global cognition (mean performance across all 12 tasks) included age, change in neural validity, education, and National Adult Reading Test (premorbid intelligence). Change in neural validity partially mediated the effect of age on change in global cognition. Our findings support the theory of age-related disintegration, linking cognitive decline to changes in neural representations over time.

Brain reserve affects the expression of cognitive reserve networks.

Cognitive reserve (CR) explains differential susceptibility of cognitive performance to neuropathology. However, as brain pathologies progress, cognitive decline occurs even in individuals with initially high CR. The interplay between the structural brain health (= level of brain reserve) and CR-related brain networks therefore requires further research. Our sample included 142 individuals aged 60-70 years. National Adult Reading Test intelligence quotient (NART-IQ) was our CR proxy. On an in-scanner Letter Sternberg task, we used ordinal trend (OrT) analysis to extract a task-related brain activation pattern (OrT slope) for each participant that captures increased expression with task load (one, three, and six letters). We assessed whether OrT slope represents a neural mechanism underlying CR by associating it with task performance and NART-IQ. Additionally, we investigated how the following brain reserve measures affect the association between NART-IQ and OrT slope: mean cortical thickness, total gray matter volume, and brain volumes proximal to the areas contained in the OrT patterns. We found that higher OrT slope was associated with better task performance and higher NART-IQ. Further, the brain reserve measures were not directly associated with OrT slope, but they affected the relationship between NART-IQ and OrT slope: NART-IQ was associated with OrT slope only in individuals with high brain reserve. The degree of brain reserve has an impact on how (and perhaps whether) CR can be implemented in brain networks in older individuals.

A randomized trial of blood donor iron repletion on red cell quality for transfusion and donor cognition and well-being.

Although altruistic regular blood donors are vital for the blood supply, many become iron deficient from donation-induced iron loss. The effects of blood donation-induced iron deficiency on red cell transfusion quality or donor cognition are unknown. In this double-blind, randomized trial, adult iron-deficient blood donors (n = 79; ferritin < 15 µg/L and zinc protoporphyrin >60 µMol/mol heme) who met donation qualifications were enrolled. A first standard blood donation was followed by the gold-standard measure for red cell storage quality: a 51-chromium posttransfusion red cell recovery study. Donors were then randomized to intravenous iron repletion (1 g low-molecular-weight iron dextran) or placebo. A second donation ∼5 months later was followed by another recovery study. Primary outcome was the within-subject change in posttransfusion recovery. The primary outcome measure of an ancillary study reported here was the National Institutes of Health Toolbox-derived uncorrected standard Cognition Fluid Composite Score. Overall, 983 donors were screened; 110 were iron-deficient, and of these, 39 were randomized to iron repletion and 40 to placebo. Red cell storage quality was unchanged by iron repletion: mean change in posttransfusion recovery was 1.6% (95% confidence interval -0.5 to 3.8) and -0.4% (-2.0 to 1.2) with and without iron, respectively. Iron repletion did not affect any cognition or well-being measures. These data provide evidence that current criteria for blood donation preserve red cell transfusion quality for the recipient and protect adult donors from measurable effects of blood donation-induced iron deficiency on cognition. This trial was registered at www.clinicaltrials.gov as NCT02889133 and NCT02990559.

Microglia measured by TSPO PET are associated with Alzheimer's disease pathology and mediate key steps in a disease progression model.

INTRODUCTION: Evidence suggests microglial activation precedes regional tau and neurodegeneration in Alzheimer's disease (AD). We characterized microglia with translocator protein (TSPO) positron emission tomography (PET) within an AD progression model where global amyloid beta (Aß) precedes local tau and neurodegeneration, resulting in cognitive impairment. METHODS: Florbetaben, PBR28, and MK-6240 PET, T1 magnetic resonance imaging, and cognitive measures were performed in 19 cognitively unimpaired older adults and 22 patients with mild cognitive impairment or mild AD to examine associations among microglia activation, Aß, tau, and cognition, adjusting for neurodegeneration. Mediation analyses evaluated the possible role of microglial activation along the AD progression model. RESULTS: Higher PBR28 uptake was associated with higher Aß, higher tau, and lower MMSE score, independent of neurodegeneration. PBR28 mediated associations between tau in early and middle Braak stages, between tau and neurodegeneration, and between neurodegeneration and cognition. DISCUSSION: Microglia are associated with AD pathology and cognition and may mediate relationships between subsequent steps in AD progression.

Simple topological task-based functional connectivity features predict longitudinal behavioral change of fluid reasoning in the RANN cohort.

Recent attention has been given to topological data analysis (TDA), and more specifically persistent homology (PH), to identify the underlying shape of brain network connectivity beyond simple edge pairings by computing connective components across different connectivity thresholds (see Sizemore et al., 2019). In the present study, we applied PH to task-based functional connectivity, computing 0-dimension Betti (B0) curves and calculating the area under these curves (AUC); AUC indicates how quickly a single connected component is formed across correlation filtration thresholds, with lower values interpreted as potentially analogous to lower whole-brain system segregation (e.g., Gracia-Tabuenca et al., 2020). One hundred sixty-three participants from the Reference Ability Neural Network (RANN) longitudinal lifespan cohort (age 20-80 years) were tested in-scanner at baseline and five-year follow-up on a battery of tests comprising four domains of cognition (i.e., Stern et al., 2014). We tested for 1.) age-related change in the AUC of the B0 curve over time, 2.) the predictive utility of AUC in accounting for longitudinal change in behavioral performance and 3.) compared system segregation to the PH approach. Results demonstrated longitudinal age-related decreases in AUC for Fluid Reasoning, with these decreases predicting longitudinal declines in cognition, even after controlling for demographic and brain integrity factors; moreover, change in AUC partially mediated the effect of age on change in cognitive performance. System segregation also significantly decreased with age in three of the four cognitive domains but did not predict change in cognition. These results argue for greater application of TDA to the study of aging.

Connectome-based predictive modelling of cognitive reserve using task-based functional connectivity.

Cognitive reserve supports cognitive function in the presence of pathology or atrophy. Functional neuroimaging may enable direct and accurate measurement of cognitive reserve which could have considerable clinical potential. The present study aimed to develop and validate a measure of cognitive reserve using task-based fMRI data that could then be applied to independent resting-state data. Connectome-based predictive modelling with leave-one-out cross-validation was applied to predict a residual measure of cognitive reserve using task-based functional connectivity from the Cognitive Reserve/Reference Ability Neural Network studies (n = 220, mean age = 51.91 years, SD = 17.04 years). This model generated summary measures of connectivity strength that accurately predicted a residual measure of cognitive reserve in unseen participants. The theoretical validity of these measures was established via a positive correlation with a socio-behavioural proxy of cognitive reserve (verbal intelligence) and a positive correlation with global cognition, independent of brain structure. This fitted model was then applied to external test data: resting-state functional connectivity data from The Irish Longitudinal Study on Ageing (TILDA, n = 294, mean age = 68.3 years, SD = 7.18 years). The network-strength predicted measures were not positively associated with a residual measure of cognitive reserve nor with measures of verbal intelligence and global cognition. The present study demonstrated that task-based functional connectivity data can be used to generate theoretically valid measures of cognitive reserve. Further work is needed to establish if, and how, measures of cognitive reserve derived from task-based functional connectivity can be applied to independent resting-state data.

Persistent homology-based functional connectivity and its association with cognitive ability: Life-span study.

Brain-segregation attributes in resting-state functional networks have been widely investigated to understand cognition and cognitive aging using various approaches [e.g., average connectivity within/between networks and brain system segregation (BSS)]. While these approaches have assumed that resting-state functional networks operate in a modular structure, a complementary perspective assumes that a core-periphery or rich club structure accounts for brain functions where the hubs are tightly interconnected to each other to allow for integrated processing. In this article, we apply a novel method, persistent homology (PH), to develop an alternative to standard functional connectivity by quantifying the pattern of information during the integrated processing. We also investigate whether PH-based functional connectivity explains cognitive performance and compare the amount of variability in explaining cognitive performance for three sets of independent variables: (1) PH-based functional connectivity, (2) graph theory-based measures, and (3) BSS. Resting-state functional connectivity data were extracted from 279 healthy participants, and cognitive ability scores were generated in four domains (fluid reasoning, episodic memory, vocabulary, and processing speed). The results first highlight the pattern of brain-information flow over whole brain regions (i.e., integrated processing) accounts for more variance of cognitive abilities than other methods. The results also show that fluid reasoning and vocabulary performance significantly decrease as the strength of the additional information flow on functional connectivity with the shortest path increases. While PH has been applied to functional connectivity analysis in recent studies, our results demonstrate potential utility of PH-based functional connectivity in understanding cognitive function.

Home Aerobic Training for Cerebellar Degenerative Diseases: a Randomized Controlled Trial.

Balance training has shown some benefits in cerebellar ataxia whereas the effects of aerobic training are relatively unknown. To determine whether a phase III trial comparing home aerobic to balance training in ambulatory patients with cerebellar ataxia is warranted, we conducted a single-center, assessor-blinded, randomized controlled trial. Nineteen subjects were randomized to aerobic training and 17 subjects to balance training. The primary outcome was improvement in ataxia as measured by the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes included safety, training adherence, and balance improvements. There were no differences between groups at baseline. Thirty-one participants completed the trial, and there were no training-related serious adverse events. Compliance to training was over 70%. There was a mean improvement in ataxia symptoms of 1.9 SARA points (SD 1.62) in the aerobic group compared to an improvement of 0.6 points (SD 1.34) in the balance group. Although two measures of balance were equivocal between groups, one measure of balance showed greater improvement with balance training compared to aerobic training. In conclusion, this 6-month trial comparing home aerobic versus balance training in cerebellar ataxia had excellent retention and adherence to training. There were no serious adverse events, and training was not interrupted by minor adverse events like falls or back pain. There was a significant improvement in ataxia symptoms with home aerobic training compared to balance training, and a phase III trial is warranted. Clinical trial registration number: NCT03701776 on October 8, 2018.

A novel causal mediation analysis approach for zero-inflated mediators.

Mediation analyses play important roles in making causal inference in biomedical research to examine causal pathways that may be mediated by one or more intermediate variables (ie, mediators). Although mediation frameworks have been well established such as counterfactual-outcomes (ie, potential-outcomes) models and traditional linear mediation models, little effort has been devoted to dealing with mediators with zero-inflated structures due to challenges associated with excessive zeros. We develop a novel mediation modeling approach to address zero-inflated mediators containing true zeros and false zeros. The new approach can decompose the total mediation effect into two components induced by zero-inflated structures: the first component is attributable to the change in the mediator on its numerical scale which is a sum of two causal pathways and the second component is attributable only to its binary change from zero to a non-zero status. An extensive simulation study is conducted to assess the performance and it shows that the proposed approach outperforms existing standard causal mediation analysis approaches. We also showcase the application of the proposed approach to a real study in comparison with a standard causal mediation analysis approach.

Longitudinal decline in semantic versus letter fluency, but not their ratio, marks incident Alzheimer's disease in Latinx Spanish-speaking older individuals.

OBJECTIVE: To compare longitudinal verbal fluency performance among Latinx Spanish speakers who develop Alzheimer's disease to those who do not develop dementia in absolute number of words produced on each task and their ratio to combine both scores. METHOD: Participants included 833 Latinx Spanish-speaking older adults from a community-based prospective cohort in Manhattan. We performed growth curve modeling to investigate the trajectories of letter and semantic fluency, and their ratio (i.e., 'semantic index'), between individuals who developed Alzheimer's disease and those who did not (i.e., controls). The semantic index quantifies the proportion of words generated for semantic fluency in relation to the total verbal fluency performance. RESULTS: Letter fluency performance did not decline in controls; we observed a linear decline in those who developed Alzheimer's disease. Semantic fluency declined in both groups and showed an increased rate of change over time in the incident Alzheimer's disease group; in comparison, the control group had a linear and slower decline. There were no group differences in the longitudinal trajectory (intercept and slope) of the semantic index. CONCLUSION: A decline in letter fluency and a more rapid and accelerating decline over time in semantic fluency distinguished people who developed Alzheimer's disease from controls. Using the semantic index was not a superior marker of incident Alzheimer's disease compared to examining the two fluency scores individually. Results suggest the differential decline in verbal fluency tasks, when evaluated appropriately, may be useful for early identification of Alzheimer's disease in Latinx Spanish speakers, a historically understudied population.

Leisure activity engagement across adulthood predicts cognitive change after five years: Do gender and age matter?

OBJECTIVE: To examine the association between leisure activity (LA) frequency and cognitive trajectories over 5 years across adulthood, and whether gender and age moderate these associations. METHOD: A total of 234 cognitively healthy adults (21-80 years) completed a LA questionnaire at baseline and neuropsychological measures at baseline and after 5 years. Latent change score analysis was applied to generate latent variables estimating changes in different cognitive domains. For a secondary analysis, LA components' scores were calculated, reflecting cognitive-intellectual, social, and physical activities. Regression analysis examined the association between baseline LA and cognitive change, and potential moderation of gender and age. In addition, we tested the influence of cortical gray matter thickness on the results. RESULTS: We found that higher LA engagement was associated with slower cognitive decline for reasoning, speed, and memory, as well as better vocabulary across two time points. Regarding LA components, higher Social-LA and Intellectual-LA predicted slower rates of cognitive decline across different domains, while Physical-LA was not associated with cognitive change. Gender, but not age, moderated some of the associations observed. Our results remained the same after controlling for cortical gray matter thickness. CONCLUSIONS: We demonstrated a protective effect of LA engagement on cognitive trajectories over 5 years, independent from demographics and a measure of brain health. The effects were in part moderated by gender, but not age. Results should be replicated in larger and more diverse samples. Our findings support cognitive reserve hypothesis and have implications for future reserve-enhancing interventions.

Retirement age and disability status as pathways to later-life cognitive impairment: Evidence from the Norwegian HUNT Study linked with Norwegian population registers.

BACKGROUND: Research shows that retirement age is associated with later-life cognition but has not sufficiently distinguished between retirement pathways. We examined how retirement age was associated with later-life dementia and mild cognitive impairment (MCI) for people who retired via the disability pathway (received a disability pension prior to old-age pension eligibility) and those who retired via the standard pathway. METHODS: The study sample comprised 7210 participants from the Norwegian Trøndelag Health Study (HUNT4 70+, 2017-2019) who had worked for at least one year in 1967-2019, worked until age 55+, and retired before HUNT4. Dementia and MCI were clinically assessed in HUNT4 70+ when participants were aged 69-85 years. Historical data on participants' retirement age and pathway were retrieved from population registers. We used multinomial regression to assess the dementia/MCI risk for women and men retiring via the disability pathway, or early (<67 years), on-time (age 67, old-age pension eligibility) or late (age 68+) via the standard pathway. RESULTS: In our study sample, 9.5% had dementia, 35.3% had MCI, and 28.1% retired via the disability pathway. The disability retirement group had an elevated risk of dementia compared to the on-time standard retirement group (relative risk ratio [RRR]: 1.64, 95% CI 1.14-2.37 for women, 1.70, 95% CI 1.17-2.48 for men). MCI risk was lower among men who retired late versus on-time (RRR, 0.76, 95% CI 0.61-0.95). CONCLUSION: Disability retirees should be monitored more closely, and preventive policies should be considered to minimize the dementia risk observed among this group of retirees.

Met-HER3 crosstalk supports proliferation via MPZL3 in MET-amplified cancer cells.

Receptor tyrosine kinases (RTKs) are recognized as targets of precision medicine in human cancer upon their gene amplification or constitutive activation, resulting in increased downstream signal complexity including heterotypic crosstalk with other RTKs. The Met RTK exhibits such reciprocal crosstalk with several members of the human EGFR (HER) family of RTKs when amplified in cancer cells. We show that Met signaling converges on HER3-tyrosine phosphorylation across a panel of seven MET-amplified cancer cell lines and that HER3 is required for cancer cell expansion and oncogenic capacity in vitro and in vivo. Gene expression analysis of HER3-depleted cells identified MPZL3, encoding a single-pass transmembrane protein, as HER3-dependent effector in multiple MET-amplified cancer cell lines. MPZL3 interacts with HER3 and MPZL3 loss phenocopies HER3 loss in MET-amplified cells, while MPZL3 overexpression can partially rescue proliferation upon HER3 depletion. Together, these data support an oncogenic role for a HER3-MPZL3 axis in MET-amplified cancers.

Physical Activity and Fitness Levels of Individuals With Ataxia: A Cross-Sectional Study.

OBJECTIVE: To investigate physical activity levels of individuals with ataxia and correlate fitness to ataxia severity. DESIGN: An observational study SETTING: An outpatient ataxia clinic in a large, tertiary, urban hospital in the US. PARTICIPANTS: Individuals with cerebellar ataxia (N=42). INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: Participants were classified as sedentary or physically active using the International Physical Activity Questionnaire-Short Form (IPAQ-SF). Maximal oxygen consumption (V̇o2max) as an indicator of fitness level was measured, and ataxia severity was determined by the Scale for the Assessment and Rating of Ataxia (SARA). Mixed effect models were used to correlate ataxia severity to fitness levels. RESULTS: Most participants (28 out of 42) lived sedentary lifestyles, and these individuals had poor fitness levels (only 67.3% of their predicted measure). The main barriers to physical activity included lack of energy, lack of time, and fear of falling. There were no differences in age, sex, disease type, disease duration, ataxia severity, fatigue level, and medication use between sedentary and active groups. Measures of V̇o2max, maximal work, maximal heart rate, and anerobic threshold demonstrated statistically significant differences between groups whereas maximal respiratory rate and expired ventilation/carbon dioxide production were similar between groups. When adjusting for age, sex, functional mobility status, and disease duration, ataxia severity was inversely correlated with fitness level in the sedentary group. There was no relationship between ataxia severity and fitness level in the 14 individuals who were physically active. CONCLUSIONS: Lower fitness levels were associated with more ataxia symptoms in the sedentary group. This relationship was not seen in individuals who were more active. Given the poor health outcomes associated with low fitness, physical activity should be encouraged in this population.

The role of neural flexibility in cognitive aging.

Studies assessing relationships between neural and cognitive changes in healthy aging have shown that a variety of aspects of brain structure and function explain a significant portion of the variability in cognitive outcomes throughout adulthood. Many studies assessing relationships between brain function and cognition have utilized time-averaged, or static functional connectivity methods to explore ways in which brain network organization may contribute to aspects of cognitive aging. However, recent studies in this field have suggested that time-varying, or dynamic measures of functional connectivity, which assess changes in functional connectivity over the course of a scan session, may play a stronger role in explaining cognitive outcomes in healthy young adults. Further, both static and dynamic functional connectivity studies suggest that there may be differences in patterns of brain-cognition relationships as a function of whether or not the participant is performing a task during the scan. Thus, the goals of the present study were threefold: (1) assess whether neural flexibility during both resting as well as task-based scans is related to participant age and cognitive performance in a lifespan aging sample, (2) determine whether neural flexibility moderates relationships between age and cognitive performance, and (3) explore differences in neural flexibility between rest and task. Participants in the study were 386 healthy adults between the ages of 20-80 who provided resting state and/or task-based (Matrix Reasoning) functional magnetic resonance imaging (fMRI) scan data as part of their participation in two ongoing studies of cognitive aging. Neural flexibility measures from both resting and task-based scans reflected the number of times each node changed network assignment, and were averaged both across the whole brain (global neural flexibility) as well as within ten somatosensory/cognitive networks. Results showed that neural flexibility was not related to participant age, and that task-based global neural flexibility, as well as task-based neural flexibility in several networks, tended to be negatively related to reaction times during the Matrix Reasoning task, however these effects did not survive strict multiple comparisons correction. Resting state neural flexibility was not significantly related to either participant age or cognitive performance. Additionally, no neural flexibility measures significantly moderated relationships between participant age and cognitive outcomes. Further, neural flexibility differed as a function of scan type, with resting state neural flexibility being significantly greater than task-based neural flexibility. Thus, neural flexibility measures computed during a cognitive task may be more meaningfully related to cognitive performance across the adult lifespan then resting state measures of neural flexibility.

Transfer learning for cognitive reserve quantification.

Cognitive reserve (CR) has been introduced to explain individual differences in susceptibility to cognitive or functional impairment in the presence of age or pathology. We developed a deep learning model to quantify the CR as residual variance in memory performance using the Structural Magnetic Resonance Imaging (sMRI) data from a lifespan healthy cohort. The generalizability of the sMRI-based deep learning model was tested in two independent healthy and Alzheimer's cohorts using transfer learning framework. Structural MRIs were collected from three cohorts: 495 healthy adults (age: 20-80) from RANN, 620 healthy adults (age: 36-100) from lifespan Human Connectome Project Aging (HCPA), and 941 adults (age: 55-92) from Alzheimer's Disease Neuroimaging Initiative (ADNI). Region of interest (ROI)-specific cortical thickness and volume measures were extracted using the Desikan-Killiany Atlas. CR was quantified by residuals which subtract the predicted memory from the true memory. Cascade neural network (CNN) models were used to train RANN dataset for memory prediction. Transfer learning was applied to transfer the T1 imaging-based model from source domain (RANN) to the target domains (HCPA or ADNI). The CNN model trained on the RANN dataset exhibited strong linear correlation between true and predicted memory based on the T1 cortical thickness and volume predictors. In addition, the model generated from healthy lifespan data (RANN) was able to generalize to an independent healthy lifespan data (HCPA) and older demented participants (ADNI) across different scanner types. The estimated CR was correlated with CR proxies such education and IQ across all three datasets. The current findings suggest that the transfer learning approach is an effective way to generalize the residual-based CR estimation. It is applicable to various diseases and may flexibly incorporate different imaging modalities such as fMRI and PET, making it a promising tool for scientific and clinical purposes.

Financial decision-making and self-awareness for financial decision-making is associated with white matter integrity in older adults.

Financial decision-making (FDM) and awareness of the integrity of one's FDM abilities (or financial awareness) are both critical for preventing financial mistakes. We examined the white matter correlates of these constructs and hypothesized that the tracts connecting the temporal-frontal regions would be most strongly correlated with both FDM and financial awareness. Overall, 49 healthy older adults were included in the FDM analysis and 44 in the financial awareness analyses. The Objective Financial Competency Assessment Inventory was used to measure FDM. Financial awareness was measured by integrating metacognitive ratings into this inventory and was calculated as the degree of overconfidence or underconfidence. Diffusion tensor imaging data were processed with Tracts Constrained by Underlying Anatomy distributed as part of the FreeSurfer analytic suite, which produced average measures of fractional anisotropy and mean diffusivity in 18 white matter tracts along with the overall tract average. As expected, FDM showed the strongest negative associations with average mean diffusivity measure of the superior longitudinal fasciculus -temporal (SLFT; r = -.360, p = .011) and -parietal (r = -.351, p = .014) tracts. After adjusting for FDM, only the association between financial awareness and average mean diffusivity measure of the right SLFT (r = .310, p = .046) was significant. Overlapping white matter tracts were involved in both FDM and financial awareness. More importantly, these preliminary findings reinforce emerging literature on a unique role of right hemisphere temporal connections in supporting financial awareness.

Baseline Differences in Long-term Survivors and Nonsurvivors of the Colorado/Columbia Fetal Implant Trial.

OBJECTIVE: This study is based on long-term follow-up of participants in a randomized double-blind sham surgery-controlled trial (1995-1999) designed to determine the effectiveness of implantation of human embryonic mesencephalic tissue containing dopamine neuron precursors into the brains of patients with advanced Parkinson's disease (PD). We investigated differences between long-term survivors and nonsurvivors at baseline in order to contribute to information regarding optimal patient selection for upcoming stem cell trials. METHOD: Forty participants were randomly assigned to receive either neural implantation or sham surgery. Thirty-four patients who ultimately received the implant were followed periodically with the most recent assessment occurring in 2015-2016. Demographic information, neurological measures, positron emission tomography (PET) imaging, neuropsychological assessments, and a personality assessment were included in the current analyses. T-tests were used to compare survivors and nonsurvivors. Logistic regression analyses examined predictors of survivorship. RESULTS: Five of six survivors were female. They were younger than nonsurvivors (p = .03) and more neuropsychologically "intact" across a broad range of cognitive areas (significance levels ranged from <.001 to .045). There were no differences between survivors and nonsurvivors off medications at baseline on neurological or PET assessments. Survivors reported more "Openness to Experience" (p = .004) than nonsurvivors. Using empirically derived predictor variables, results of logistic regression analyses indicated that Animal Naming (cognitive task) and Openness to Experience (personality variable) were the strongest predictors of survivorship. CONCLUSIONS: Variables to consider when selecting participants for future cell-based therapies include being "intact" neuropsychologically, level of Openness to Experience, younger age, and inclusion of women.

Segregation of functional networks is associated with cognitive resilience in Alzheimer's disease.

Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer's disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P = 0.007). Similarly, for patients with sporadic Alzheimer's disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P = 0.001) and episodic memory (P = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer's disease.

Patterns of tau pathology identified with 18 F-MK-6240 PET imaging.

INTRODUCTION: Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of 18 F-MK-6240 in a clinical sample and determined the relationships among 18 F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers. METHODS: Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aß)42 , tau, and phosphorylated tau (p-tau). RESULTS: 18 F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aß42 . 18 F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of 18 F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants. DISCUSSION: 18 F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.