The Caenorhabditis elegans protein SOC-3 permits an alternative mode of signal transduction by the EGL-15 FGF receptor.

Fibroblast Growth Factors and their receptors (FGFRs) comprise a cell signaling module that can stimulate signaling by Ras and the kinases Raf, MEK, and ERK to regulate animal development and homeostatic functions. In Caenorhabditis elegans, the sole FGFR ortholog EGL-15 acts with the GRB2 ortholog SEM-5 to promote chemoattraction and migration by the sex myoblasts (SMs) and fluid homeostasis by the hypodermis (Hyp7). Cell-specific differences in EGL-15 signaling were suggested by the phenotypes caused by egl-15(n1457), an allele that removes a region of its C-terminal domain (CTD) known to bind SEM-5. To determine how mutations altered EGL-15 activity in the SMs and Hyp7, we used the kinase reporter ERK-KTR to measure activation of the ERK ortholog MPK-1. Consequences of egl-15(n1457) were cell-specific, resulting in loss of MPK-1 activity in the SMs and elevated activity in Hyp7. Previous studies of Hyp7 showed that loss of the CLR-1 phosphatase causes a fluid homeostasis defect termed "Clear" that is suppressed by reduction of EGL-15 signaling, a phenotype termed "Suppressor of Clear" (Soc). To identify mechanisms that permit EGL-15 signaling in Hyp7, we conducted a genetic screen for Soc mutants in the clr-1; egl-15(n1457) genotype. We report the identification of SOC-3, a protein with putative SEM-5-binding motifs and PH and PTB domains similar to DOK and IRS proteins. In combination with the egl-15(n1457) mutation, loss of either soc-3, the GAB1 ortholog soc-1, or the SHP2 ortholog ptp-2, reduced MPK-1 activation. We generated alleles of soc-3 to test the requirement for the SEM-5-binding motifs, finding that residue Tyr356 is required for function. We propose that EGL-15-mediated SM chemoattraction relies solely on the direct interaction between SEM-5 and the EGL-15 CTD. In Hyp7, EGL-15 signaling uses two mechanisms: the direct SEM-5 binding mechanism; and an alternative, CTD-independent mechanism involving SOC-3, SOC-1, and PTP-2. This work demonstrates that FGF signaling uses distinct, tissue-specific mechanisms in development, and identifies SOC-3 as a potential adaptor that facilitates Ras pathway activation by FGFR.

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.

Cognitive Polygenic Index is Associated with Occupational Complexity over and above Brain Morphometry.

Although the impact of occupation on cognitive skills has been extensively studied, there is limited research examining if genetically predicted cognitive score may influence occupation. We examined the association between Cognitive Polygenic Index (PGI) and occupation, including the role of brain measures. Participants were recruited for the Reference Ability Neural Network and the Cognitive Reserve studies. Occupational complexity ratings for Data, People, or Things came from the Dictionary of Occupational Titles. A previously-created Cognitive PGI and linear regression models were used for the analyses. Age, sex, education, and the first 20 genetic Principal Components (PCs) of the sample were covariates. Total cortical thickness and total gray matter volume were further covariates. We included 168 white-ethnicity participants, 20-80 years old. After initial adjustment, higher Cognitive PGI was associated with higher Data complexity (B=-0.526, SE = 0.227, Beta= -0.526 p = 0.022, R2 = 0.259) (lower score implies higher complexity). Associations for People or Things were not significant. After adding brain measures, association for Data remained significant (B=-0.496, SE: 0.245, Beta= -0.422, p = 0.045, R2 = 0.254). Similarly, for a further, fully-adjusted analysis including all the three occupational complexity measures (B=-0.568, SE = 0.237, Beta= -0.483, p = 0.018, R2 = 0.327). Cognitive genes were associated with occupational complexity over and above brain morphometry. Working with Data occupational complexity probably acquires higher cognitive status, which can be significantly genetically predetermined.

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.

Personality traits and cognitive reserve-High openness benefits cognition in the presence of age-related brain changes.

Cognitive reserve explains differential susceptibility of cognitive performance to neuropathology. We investigated whether certain personality traits underlie cognitive reserve and are accordingly associated with better cognition and less cognitive decline in the presence of age-related brain changes. We included healthy adults aged 19-80 years for cross-sectional (N=399) and longitudinal (N=273, mean follow-up time=5 years, SD=0.7 years) analyses. Assessment of the BIG5 personality traits openness, conscientiousness, extraversion, agreeableness, and neuroticism was questionnaire-based. Each cognitive domain (perceptual speed, memory, fluid reasoning, vocabulary) was measured with up to six tasks. Cognitive domain-specific brain status variables were obtained by combining 77 structural brain measures into single scores using elastic net regularization. These brain status variables explained up to 43.1% of the variance in cognitive performance. We found that higher openness was associated with higher fluid reasoning and better vocabulary after controlling for brain status, age, and sex. Further, lower brain status was associated with a greater decline in perceptual speed only in individuals with low openness. We conclude that high openness benefits cognitive reserve.

The relationship between cortical thickness and white matter hyperintensities in mid to late life.

White matter hyperintensities (WMH) are associated with cortical thinning. Although they are primarily detected in older participants, these lesions can appear in younger and midlife individuals. Here, we tested whether WMH are associated with cortical thinning in relatively younger (26-50 years) and relatively older (58-84) participants who were free of dementia, and how these associations are moderated by WMH localization. WMH were automatically quantified and categorized according to the localization of three classes of white matter tracts: association, commissural and projection fibers. Mediation analyses were used to infer whether differences in cortical thickness between younger and older participants were explained by WMH. Our results revealed that total WMH explained between 20.6 % and 65.5 % of the effect of age on cortical thickness in AD-signature regions including the lateral temporal lobes and supramarginal gyrus, among others. This mediation was slightly stronger for projection WMH, although it was still significant for association and commissural WMH. These results suggest that there is an interplay between vascular and AD causes of cognitive impairment that starts at younger ages.

Sleep problems as predictors of cognitive decline in essential tremor: A prospective longitudinal cohort study.

BACKGROUND: There is growing evidence that essential tremor (ET) patients are at high risk of cognitive impairment. Predictors of cognitive impairment have not been studied extensively. There is evidence from cross-sectional studies that sleep dysregulation is associated with cognitive dysfunction in ET, but longitudinal studies of the impact of sleep disruption on cognitive change have not been conducted. We investigated the extent to which sleep problems predict cognitive change in patients with ET. METHODS: ET cases enrolled in a prospective, longitudinal study of cognitive performance. Sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI). Cognitive abilities across five domains (memory, executive function, attention, language, and visuospatial ability), and a global cognitive score (mean of the domains) were extracted from an extensive neuropsychological assessment. Generalized estimated equations were used to examine the association between baseline sleep problems and cognitive changes over three follow-up assessments each spaced 18 months apart. RESULTS: The 188 non-demented ET cases had a mean age of 77.7 ± 9.5 years. Longer sleep latency was associated with longitudinal decline in executive function (p = 0.038), and marginally with longitudinal decline in global cognitive performance (p = 0.075). After excluding 29 cases with mild cognitive impairment, results were similar. CONCLUSION: Cognitively healthy people with ET who have longer sleep latency had greater declines in executive function during prospective follow-up. Early detection of, and possibly intervention for, abnormal sleep latency may protect against certain aspects of cognitive decline in ET patients.

Childhood engagement in cognitively stimulating activities moderates relationships between brain structure and cognitive function in adulthood.

Greater engagement in cognitively stimulating activities (CSA) during adulthood has been shown to protect against neurocognitive decline, but no studies have investigated whether CSA during childhood protects against effects of brain changes on cognition later in life. The current study tested the moderating role of childhood CSA in the relationships between brain structure and cognitive performance during adulthood. At baseline (N=250) and 5-year follow-up (N=204) healthy adults aged 20-80 underwent MRI to assess four structural brain measures and completed neuropsychological tests to measure three cognitive domains. Participants were categorized into low and high childhood CSA based on self-report questionnaires. Results of multivariable linear regressions analyzing interactions between CSA, brain structure, and cognition showed that higher childhood CSA was associated with a weaker relationship between cortical thickness and memory at baseline, and attenuated the effects of change in cortical thickness and brain volume on decline in processing speed over time. These findings suggest higher CSA during childhood may mitigate the effects of brain structure changes on cognitive function later in life.

In vivo tau is associated with change in memory and processing speed, but not reasoning, in cognitively unimpaired older adults.

The relationship between tau deposition and cognitive decline in cognitively healthy older adults is still unclear. The tau PET tracer 18F-MK-6240 has shown favorable imaging characteristics to identify early tau deposition in aging. We evaluated the relationship between in vivo tau levels (18F-MK-6240) and retrospective cognitive change over 5 years in episodic memory, processing speed, and reasoning. For tau quantification, a set of regions of interest (ROIs) was selected a priori based on previous literature: (1) total-ROI comprising selected areas, (2) medial temporal lobe-ROI, and (3) lateral temporal lobe-ROI and cingulate/parietal lobe-ROI. Higher tau burden in most ROIs was associated with a steeper decline in memory and speed. There were no associations between tau and reasoning change. The novelty of this finding is that tau burden may affect not only episodic memory, a well-established finding but also processing speed. Our finding reinforces the notion that early tau deposition in areas related to Alzheimer's disease is associated with cognitive decline in cognitively unimpaired individuals, even in a sample with low amyloid-ß pathology.

Cognitive reserve proxies are associated with age-related cognitive decline - Not age-related gait speed decline.

Cognition and gait share brain substrates in aging and dementia. Cognitive reserve (CR) allows individuals to cope with brain pathology and delay cognitive impairment and dementia. Yet, evidence for that CR is associated with age-related cognitive decline is mixed, and evidence for that CR is associated with age-related gait decline is limited. In 1,079 older (M Age = 75.4 years; 56.0% women) LonGenity study participants without dementia at baseline and up to 12 years of annual follow-up (M follow-up = 3.9 years, SD = 2.5 years), high CR inferred from cognitive (education years), physical (number of blocks walked per day; weekly physical activity days), and social (volunteering/working; living with someone) proxies were associated with slower rates of age-related decline in global cognition - not gait speed decline. Thus, cognitive, physical, and social CR proxies are associated with cognitive decline in older adults without dementia. The multifactorial etiology and earlier decline in gait than cognition may render it less modifiable by CR proxies later in life.

Trajectories of Occupational Cognitive Demands and Risk of Mild Cognitive Impairment and Dementia in Later Life: The HUNT4 70+ Study.

BACKGROUND AND OBJECTIVES: The cognitive reserve hypothesis posits that cognitively stimulating work delays the onset of mild cognitive impairment (MCI) and dementia. However, the effect of occupational cognitive demands across midlife on the risk of these conditions is unclear. METHODS: Using a cohort study design, we evaluated the association between registry-based trajectories of occupational cognitive demands from ages 30-65 years and clinically diagnosed MCI and dementia in participants in the HUNT4 70+ Study (2017-19). Group-based trajectory modeling identified trajectories of occupational cognitive demands, measured by the routine task intensity (RTI) index (lower RTI indicates more cognitively demanding occupation) from the Occupational Information Network. Multinomial regression was implemented to estimate the relative risk ratios (RRRs) of MCI and dementia, after adjusting for age, sex, education, income, baseline hypertension, obesity, diabetes, psychiatric impairment, hearing impairment, loneliness, smoking status, and physical inactivity assessed at HUNT1-2 in 1984-1986 and 1995-1997. To handle missing data, we used inverse probability weighting to account for nonparticipation in cognitive testing and multiple imputation. RESULTS: Based on longitudinal RTI scores for 305 unique occupations, 4 RTI trajectory groups were identified (n = 7,003, 49.8% women, age range 69-104 years): low RTI (n = 1,431, 20.4%), intermediate-low RTI (n = 1,578, 22.5%), intermediate-high RTI (n = 2,601, 37.1%), and high RTI (n = 1,393, 19.9%). Participants in the high RTI group had a higher risk of MCI (RRR 1.74, 95% CI 1.41-2.14) and dementia (RRR 1.37, 95% CI 1.01-1.86), after adjusting for age, sex, and education compared with participants in the low RTI group. In a sensitivity analysis, controlling for income and baseline health-related factors, the point estimates were not appreciably changed (RRR 1.66, 95% CI 1.35-2.06 for MCI, and RRR 1.31, 95% CI 0.96-1.78 for dementia). DISCUSSION: People with a history of cognitively stimulating occupations during their 30s, 40s, 50s, and 60s had a lower risk of MCI and dementia older than 70 years, highlighting the importance of occupational cognitive stimulation during midlife for maintaining cognitive function in old age. Further research is required to pinpoint the specific occupational cognitive demands that are most advantageous for maintaining later-life cognitive function.

Detection of neurophysiological markers of cognitive reserve: an EEG study.

Background and objectives: Cognitive reserve (CR) is a property of the brain that allows for better-than-expected cognitive performance relative to the degree of brain change over the course of life. However, neurophysiological markers of CR remain under-investigated. Electroencephalography (EEG) features may function as suitable neurophysiological markers of CR. To assess this, we investigated whether the dorsal attention network (DAN) and ventral attention network (VAN) activities, as measured during resting-state EEG, moderate the relationship between hippocampal volume and episodic memory. Methods: Participants were recruited as part of the National Center for Geriatrics and Gerontology-Study of Geriatric Syndromes. Hippocampal volume was determined using magnetic MRI, and episodic memory was measured using word lists. After testing the effect of hippocampal volume on memory performance using multiple regression analysis, we evaluated the interactions between hippocampal volume and DAN and VAN network activities. We further used the Johnson-Neyman technique to quantify the moderating effects of DAN and VAN network activities on the relationship between hippocampal volume and word list memory, as well as to identify specific ranges of DAN and VAN network activity with significant hippocampal-memory association. Results: A total of 449 participants were included in this study. Our analysis revealed significant moderation of DAN with a slope of ß = -0.00012 (95% CI: -0.00024; -0.00001, p = 0.040), and VAN with a slope of ß = 0.00014 (95% CI: 0.00001; 0.00026, p = 0.031). Further, we found that a larger hippocampal volume was associated with improved memory performance, and that this association became stronger as the DAN activity decreased until a limit of DAN activity of 944.9, after which the hippocampal volume was no longer significantly related to word-list memory performance. For the VAN, we found that a higher hippocampal volume was more strongly associated with better memory performance when VAN activity was higher. However, when VAN activity extended beyond -914.6, the hippocampal volume was no longer significantly associated with word-list memory. Discussion: Our results suggest that attentional networks help to maintain memory performance in the face of age-related structural decline, meeting the criteria for the neural implementation of cognitive reserve.

Remote Associations Between Tau and Cortical Amyloid-ß Are Stage-Dependent.

Background: Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-ß (Aß) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aß and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aß deposition. Methods: Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aß associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aß association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aß in lateral temporal lobe regions. The strongest tau-Aß associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aß (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aß associations were no longer significant. Conclusions: The results indicate that associations between tau and Aß are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD.

Neurophysiological markers in community-dwelling older adults with mild cognitive impairment: an EEG study.

BACKGROUND: Neurodegeneration and structural changes in the brain due to amyloid deposition have been observed even in individuals with mild cognitive impairment (MCI). EEG measurement is considered an effective tool because it is noninvasive, has few restrictions on the measurement environment, and is simple and easy to use. In this study, we investigated the neurophysiological characteristics of community-dwelling older adults with MCI using EEG. METHODS: Demographic characteristics, cognitive function, physical function, resting-state MRI and electroencephalogram (rs-EEG), event-related potentials (ERPs) during Simon tasks, and task proportion of correct responses and reaction times (RTs) were obtained from 402 healthy controls (HC) and 47 MCI participants. We introduced exact low-resolution brain electromagnetic tomography-independent component analysis (eLORETA-ICA) to assess the rs-EEG network in community-dwelling older adults with MCI. RESULTS: A lower proportion of correct responses to the Simon task and slower RTs were observed in the MCI group (p < 0.01). Despite no difference in brain volume between the HC and MCI groups, significant decreases in dorsal attention network (DAN) activity (p < 0.05) and N2 amplitude of ERP (p < 0.001) were observed in the MCI group. Moreover, DAN activity demonstrated a correlation with education (Rs = 0.32, p = 0.027), global cognitive function (Rs = 0.32, p = 0.030), and processing speed (Rs = 0.37, p = 0.010) in the MCI group. The discrimination accuracy for MCI with the addition of the eLORETA-ICA network ranged from 0.7817 to 0.7929, and the area under the curve ranged from 0.8492 to 0.8495. CONCLUSIONS: The eLORETA-ICA approach of rs-EEG using noninvasive and relatively inexpensive EEG demonstrates specific changes in elders with MCI. It may provide a simple and valid assessment method with few restrictions on the measurement environment and may be useful for early detection of MCI in community-dwelling older adults.