Comprehensive assessment of TDP-43 neuropathology data in the National Alzheimer's Coordinating Center database.

TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related pathology data in the National Alzheimer's Coordinating Center (NACC) in two parts: (I) availability of assessments, and (II) associations with clinical diagnoses and other neuropathologies in those with all TDP-43 measures available. Part I: Of 4326 participants with neuropathology data collected using forms that included TDP-43 assessments, data availability was highest for HS-A (97%) and ALS (94%), followed by FTLD-TDP (83%). Regional TDP-43 pathologic assessment was available for 77% of participants, with hippocampus the most common region. Availability for the TDP-43-related measures increased over time, and was higher in centers with high proportions of participants with clinical FTLD. Part II: In 2142 participants with all TDP-43-related assessments available, 27% of participants had LATE-NC, whereas ALS-TDP or FTLD-TDP (ALS/FTLD-TDP) was present in 9% of participants, and 2% of participants had TDP-43 related to other pathologies ("Other TDP-43"). HS-A was present in 14% of participants, of whom 55% had LATE-NC, 20% ASL/FTLD-TDP, 3% Other TDP-43, and 23% no TDP-43. LATE-NC, ALS/FTLD-TDP, and Other TDP-43, were each associated with higher odds of dementia, HS-A, and hippocampal atrophy, compared to those without TDP-43 pathology. LATE-NC was associated with higher odds for Alzheimer's disease (AD) clinical diagnosis, AD neuropathologic change (ADNC), Lewy bodies, arteriolosclerosis, and cortical atrophy. ALS/FTLD-TDP was associated with higher odds of clinical diagnoses of primary progressive aphasia and behavioral-variant frontotemporal dementia, and cortical/frontotemporal lobar atrophy. When using NACC data for TDP-43-related analyses, researchers should carefully consider the incomplete availability of the different regional TDP-43 assessments, the high frequency of participants with ALS/FTLD-TDP, and the presence of other forms of TDP-43 pathology.

Characterization of hippocampal sclerosis of aging and its association with other neuropathologic changes and cognitive deficits in the oldest-old.

Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer's disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion. We compared this traditional measure against our novel quantitative measure for studying the relationship between HS-A and other neuropathologies and cognitive impairment. We included 409 participants from The 90+ study with neuropathological examination and longitudinal neuropsychological assessments. In those with HS-A, we examined digitized H&E and LFB stained hippocampal slides. The length of HS-A in each subfield of hippocampus and subiculum, each further divided into three subregions, was measured using Aperio eSlide Manager. For each subregion, the proportion affected by HS-A was calculated. Using regression models, both traditional/binary and quantitative measures were used to study the relationship between HS-A and other neuropathological changes and cognitive outcomes. HS-A was present in 48 (12%) of participants and was always focal, primarily affecting CA1 (73%), followed by subiculum (9%); overlapping pathology (subiculum and CA1) affected 18% of individuals. HS-A was more common in the left (82%) than the right (25%) hemisphere and was bilateral in 7% of participants. HS-A traditional/binary assessment was associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC; OR = 3.45, p < 0.001) and aging-related tau astrogliopathy (ARTAG; OR = 2.72, p = 0.008). In contrast, our quantitative approach showed associations between the proportion of HS-A (CA1/subiculum/combined) and LATE-NC (p = 0.001) and arteriolosclerosis (p = 0.005). While traditional binary assessment of HS-A was associated with impaired memory (OR = 2.60, p = 0.007), calculations (OR = 2.16, p = 0.027), and orientation (OR = 3.56, p < 0.001), our quantitative approach revealed additional associations with impairments in language (OR = 1.33, p = 0.018) and visuospatial domains (OR = 1.37, p = 0.006). Our novel quantitative method revealed associations between HS-A and vascular pathologies and impairment in cognitive domains that were not detected using traditional/binary measures.

LATE-NC staging in routine neuropathologic diagnosis: an update.

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

Dissociation and false memory: the moderating role of trauma and cognitive ability.

The term dissociation is often used to refer to a diverse range of psychological symptoms, including perceptual impairments, emotional detachment, and memory fragmentation. In the present study, we examined whether there was a relation between participants' self-reports of dissociative experiences and their memory performance in the Deese-Roediger-McDermott (DRM) paradigm-a laboratory-based procedure that is frequently used to investigate false memory. University students (N = 298) completed the Dissociative Experiences Scale (DES) and the Traumatic Life Events Questionnaire (TLEQ). Participants were also administered a standardised intelligence test (Shipley-2), and they were tested in the DRM paradigm. Overall, experiencing trauma and dissociation, as well as lower levels of cognitive ability, were associated with higher false memory. These findings are discussed in the context of the activation monitoring theory of DRM false memory.

Co-delivery of rituximab targeted curcumin and imatinib nanostructured lipid carriers in non-Hodgkin lymphoma cells.

The aim of the present study was production of nanostructured lipid carriers (NLCs) of curcumin and imatinib for co-administration in non-Hodgkin lymphoma cells. NLCs were prepared and conjugated to rituximab to target CD20 receptors of lymphoma cell lines. Oleic acid or Labrafac and glyceryl monostearate or lecithin were used for production of NLCs. The antibody coupling efficiency to NLCs and their physical characteristics were studied. The cytotoxicity of NLCs on Jurkat T cells (CD20 receptor negative) and Ramos B cells (CD20 receptor positive) was studied by MTT assay. The cellular uptake was determined by fluorescent microscopy. The results indicated both curcumin and imatinib targeted NLCs had a significant cytotoxic effect much higher than the free drugs and non-targeted NLCs on Ramos cells. In both cell lines, the cytotoxicity of the co-administrated drugs was significantly higher than each drug alone. In Ramos cells the co-administration of curcumin (15 µg/ml)/imatinib (5 µg/ml) decreased the free curcumin IC50 from 8.3 ± 0.9 to 1.9 ± 0.2 µg/ml, and curcumin targeted NLCs from 6.7 ± 0.1 to 1.3 ± 0.2 µg/ml. In this case the IC50 of imatinib was reduced from 11.1 ± 0.7 to 2.3 ± 0.1 µg/ml and imatinib targeted NLCs from 4.3 ± 0.1 to 1.4 ± 0.0 µg/ml. The co-administration of ritoximab conjugated NLCs of curcumin and imatinib may enhance cytotoxicity of imatinib in treatment of non-Hodgkin lymphoma.

Utility of MRI in the identification of hippocampal sclerosis of aging.

INTRODUCTION: Hippocampal sclerosis of aging (HS) is a common pathology often misdiagnosed as Alzheimer's disease. We tested the hypothesis that participants with HS would have a magnetic resonance imaging (MRI)-detectable hippocampal pattern of atrophy distinct from participants without HS, both with and without Alzheimer's disease neuropathology (ADNP). METHODS: Query of the National Alzheimer's Coordinating Center database identified 198 participants with MRI and autopsy. Hippocampal subfields were segmented with FreeSurfer v6. Analysis of covariance for subfield volumes compared HS+ participants to those without HS, both with ADNP (HS-/ADNP+) and without (HS-/ADNP-). RESULTS: HS+ participants (N = 27, 14%) showed atrophied cornu ammonis 1 (CA1; left P < .001, ηp2  = 0.14; right P = .001, ηp2  = 0.09) and subiculum (left P < .001, ηp2  = 0.139; right P = .001, ηp2  = 0.085) compared to HS-/ADNP+ (N = 100, 51%). Compared to HS-/ADNP- (N = 71, 36%), HS+ also had atrophy in subiculum (left P < .001, ηp2  = 0.235; right P = .002, ηp2  = 0.137) and CA1 (left P < .001, ηp2  = 0.137; right P = .006, ηp2  = 0.070). DISCUSSION: Subiculum and CA1 atrophy from clinical MRI may be a promising in vivo biomarker for HS.

Positron emission tomography-guided magnetic resonance spectroscopy in Alzheimer disease.

OBJECTIVE: To determine whether the level of metabolites in magnetic resonance spectroscopy (MRS) is a representative marker of underlying pathological changes identified in positron emission tomographic (PET) images in Alzheimer disease (AD). METHODS: We performed PET-guided MRS in cases of probable AD, mild cognitive impairment (MCI), and healthy controls (HC). All participants were imaged by 11 C-Pittsburgh compound B (11 C-PiB) and 18 F-fluorodeoxyglucose (18 F-FDG) PET followed by 3T MRS. PET images were assessed both visually and using standardized uptake value ratios (SUVRs). MRS voxels were placed in regions with maximum abnormality on amyloid (Aß+) and FDG (hypometabolic) areas on PET scans. Corresponding normal areas were selected in controls. The ratios of total N-acetyl (tNA) group, myoinositol (mI), choline, and glutamate + glutamine over creatine (Cr) were compared between these regions. RESULTS: Aß + regions had significantly higher (p = 0.02) mI/Cr and lower tNA/Cr (p = 0.02), whereas in hypometabolic areas only tNA/Cr was reduced (p = 0.003). Multiple regression analysis adjusting for sex, age, and education showed mI/Cr was only associated with 11 C-PiB SUVR (p < 0.0001). tNA/Cr, however, was associated with both PiB (p = 0.0003) and 18 F-FDG SUVR (p = 0.006). The level of mI/Cr was not significantly different between MCI and AD (p = 0.28), but tNA/Cr showed significant decline from HC to MCI to AD (p = 0.001, p = 0.04). INTERPRETATION: mI/Cr has significant temporal and spatial associations with Aß and could potentially be considered as a disease state biomarker. tNA is an indicator of early neurodegenerative changes and might have a role as disease stage biomarker and also as a valuable surrogate marker for treatment response. Ann Neurol 2018;83:771-778.

A new fractional model and optimal control of a tumor-immune surveillance with non-singular derivative operator.

In this paper, we present a new fractional-order mathematical model for a tumor-immune surveillance mechanism. We analyze the interactions between various tumor cell populations and immune system via a system of fractional differential equations (FDEs). An efficient numerical procedure is suggested to solve these FDEs by considering singular and nonsingular derivative operators. An optimal control strategy for investigating the effect of chemotherapy treatment on the proposed fractional model is also provided. Simulation results show that the new presented model based on the fractional operator with Mittag-Leffler kernel represents various asymptomatic behaviors that tracks the real data more accurately than the other fractional- and integer-order models. Numerical simulations also verify the efficiency of the proposed optimal control strategy and show that the growth of the naive tumor cell population is successfully declined.

Functional recovery in older adults with schizophrenia: A national interRAI study.

BACKGROUND: The concept of recovery for people with schizophrenia (PwS) is still a matter of debate. Growing numbers of PwS living to older age calls for examination of their disease trajectories with a focus on recovery. AIM: To compare two groups of PwS (good wellbeing; poor wellbeing) on several psychosocial variables associated with social wellbeing to identify interventions that support functional recovery. METHOD: Data was drawn from participants from across New Zealand (NZ), who had received a formal diagnosis of Schizophrenia; were living independently in the community, and who had undergone their first International Resident Assessment Instrument (interRAI) assessment from 2012 to 2022. We compared two groups of PwS (good social wellbeing; poor social wellbeing) examining associations with demographic and psychosocial variables. RESULTS: We compared interRAI assessments for: 'poor psychosocial wellbeing' (n = 1,378; 67%; 56% female; 70.5% 65 years and over; 36.1% never married); and 'good psychosocial wellbeing' (n = 693; 33%; 61.1% female; 78.1% 65 years and over; 29.8% never married; n = 549 did not have sufficient social wellbeing data to be included). We found significant associations between social wellbeing and depression, disruptive behaviour, decision making, self-expression, understanding verbal information, activity level, self-reported health and medication adherence. Logistical regression showed depression (ß = .84, p < .001, Wald = 51.01, Exp(B) = 2.31) and mild disruptive behaviour (ß = .63, p = .002, Wald = 9.26, Exp(B) = 0.53) were the only predictors of poor social wellbeing. Those who reported some degree of depressive symptoms were 2.31 (CI [1.84, 2.91]) more likely to be in the poor social wellbeing group. CONCLUSIONS: A significant minority (33.5%) of older PwS enjoy positive social wellbeing. Several psychosocial variables are associated with wellbeing. By addressing the comorbidity of depressive symptoms, we may be able to improve wellbeing for older PwS.

Alzheimer's Disease Biomarker Decision-Making among Patients with Mild Cognitive Impairment and Their Care Partners.

BACKGROUND: Alzheimer's disease (AD) biomarker tests can be ordered as part of the diagnostic workup of patients with mild cognitive impairment (MCI). Little is known about how patients with MCI and their care partners decide whether to pursue testing. OBJECTIVE: To examine factors that influence AD biomarker testing decisions among patients with MCI and their care partners. DESIGN: We performed structured research interviews with patients with MCI and their study partners to assess the importance of eight factors in the decision whether to undergo AD biomarker testing (6-point Likert scale; 1-extremely unimportant to 6-extremely important): cost, fear of testing procedures, learning if AD is the cause of cognitive problems, concern about health insurance, instructing future planning, informing treatment decisions, family members' opinions, and doctor recommendation. SETTING: Two researchers administered interviews with participants in-person (i.e., participant home, research center) or remotely (i.e., telephone, video-conference). PARTICIPANTS: We completed interviews with 65 patients with a diagnosis of MCI and 57 study partners, referred by dementia specialist clinicians from the University of California, Irvine health system. MEASUREMENTS: We used generalized estimating equations (GEE) to examine the mean importance of each factor among patients and study partners, and the mean difference in importance of each factor within dyads. RESULTS: One third of participants reported the patient had previously undergone AD biomarker testing. Fifty-five percent of patients and 65% of study partners who reported no previous testing indicated a desire for the patient to be tested. GEE analyses found that patients and study partners rated the following factors with highest importance: informing treatment decisions (mean score 5.29, 95% CI: 5.06, 5.52 for patients; mean score 5.56, 95% CI: 5.41, 5.72 for partners); doctor recommendation (4.94, 95% CI: 4.73, 5.15 for patients; 5.16, 95% CI: 4.97, 5.34 for partners); and instructing future planning (4.88, 95% CI: 4.59, 5.16 for patients; 5.11, 95% CI: 4.86, 5.35 for partners). High dyadic agreement was observed for all factors except fear of testing, which patients rated with lower importance than their study partners. CONCLUSIONS: Biomarker testing for AD in patients with MCI is a rapidly evolving practice and limited data exist on patient perspectives. In this study, most patients and their care partners were interested in testing to help inform treatment decisions and to plan for the future. Participants placed high importance on clinician recommendations for biomarker testing, highlighting the need for clear communication and education on the options, limitations, risks, and benefits of testing.

Predicting rejection of emerging contaminants through RO membrane filtration based on ANN-QSAR modeling approach: trends in molecular descriptors and structures towards rejections.

In this work, a quantitative structure-activity relationship (QSAR) study was performed on a set of emerging contaminants (ECs) to predict their rejections by reverse osmosis membrane (RO). A wide range of molecular descriptors was calculated by Dragon software for 72 ECs. The QSAR data was analyzed by an artificial neural network method (ANN), in which four out of 3000 theoretical molecular descriptors were chosen and their significance was computed based on the Garson method. The significance trends of descriptors were as follows in descending order: ESpm14u > R2e > SIC1 > EEig03d. The selected descriptors were ranked based on their importance and then an explorative study was conducted on the QSAR data to show the trends in molecular descriptors and structures toward the rejections values of ECs. The MLR algorithm was used to make a linear model and the results were compared with those of the nonlinear ANN algorithm. The comparison results revealed it is necessary to apply the ANN model to this data with non-linear properties. For the whole dataset, the correlation coefficient (R2) and residual mean squared error (RMSE) of the ANN and MLR methods were 0.9528, 6.4224; and 0.8753, 11.3400, respectively. The comparison results showed the superiority of ANN modeling in the analysis of ECs' QSAR data.

Association of vascular and degenerative brain pathologies and past medical history from the National Alzheimer's Coordinating Center Database.

The relationship between past medical histories (PMH) and dementia-related neuropathologies is not well understood. Using the National Alzheimer's Coordinating Center (NACC) database, we explored the relationship between patient-reported PMH and various vascular and degenerative neuropathologies. We examined the following PMH: transient ischemic attack (TIA), stroke, traumatic brain injury, seizures, hypertension, cardiovascular events, hypercholesterolemia, B12 deficiency, diabetes mellitus, and thyroid disease. We dichotomized the following neuropathologies: atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy (CAA), Alzheimer disease neuropathology (ADNP), Lewy bodies (LB), hippocampal sclerosis, frontotemporal lobar degeneration (FTLD), and TAR DNA-binding protein-43 (TDP-43). Separate logistic regression models assessed the relationship between the outcome of individual neuropathologies and all PMHs. Additional logistic regressions were stratified by sex to further examine these associations. Hypertension history was associated with an increased likelihood of atherosclerosis (OR = 1.7) and arteriolosclerosis (OR = 1.3), but decreased odds of ADNP (OR = 0.81), CAA (OR = 0.79), and LB (OR = 0.78). History of TIA was associated with an increased likelihood of atherosclerosis (OR = 1.3) and arteriolosclerosis (OR = 1.4) and lower odds of ADNP (OR = 0.72). Seizure history was associated with an increased likelihood of ADNP (OR = 1.9) and lower odds of FTLD (OR = 0.49). Hypertension history was associated with a greater likelihood of vascular pathologies yet a lower likelihood of ADNP and other neurodegenerative pathologies.

Longitudinal hippocampal atrophy in hippocampal sclerosis of aging.

Hippocampal sclerosis of aging (HS-A) is a common degenerative neuropathology in older individuals and is associated with dementia. HS-A is characterized by disproportionate hippocampal atrophy at autopsy but cannot be diagnosed during life. Therefore, little is known about the onset and progression of hippocampal atrophy in individuals with HS-A. To better understand the onset and progression of hippocampal atrophy in HS-A, we examined longitudinal hippocampal atrophy using serial MRI in participants with HS-A at autopsy (HS-A+, n = 8) compared to participants with limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) without HS-A (n = 13), Alzheimer's disease neuropathologic change (ADNC) without HS-A or LATE-NC (n = 16), and those without these pathologies (n = 7). We found that participants with HS-A had lower hippocampal volumes compared to the other groups, and this atrophy preceded the onset of dementia. There was also some evidence that rates of hippocampal volume loss were slightly slower in those with HS-A. Together, these results suggest that the disproportionate hippocampal atrophy seen in HS-A may begin early prior to dementia.

LATE and potential estrogen-related risk factors collected 30 years earlier: The 90+ Study.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a recently described neuropathological construct associated with dementia. This study aimed to investigate in an autopsy study, LATE-NC and its associations with potential estrogen-related risk factors collected about 30 years before death. Participants were part of The 90+ Study and had, as part of the Leisure World Cohort Study, provided information on menstrual and reproductive variables and details of use of estrogen replacement therapy (ERT). No menstrual and reproductive variable showed an association with LATE-NC. Use of ERT, especially long-term use (15+ years) and more recent use (within 1 year of completing the questionnaire), was associated with reduced risk. The odds were significantly lower for long-term (0.39, 95% confidence interval [CI]: 0.16-0.95) and recent use (0.39, 95% CI: 0.16-0.91) compared with no use. In conclusion, we found that women who reported long-term ERT in their 50s and 60s had a significantly reduced odds of harboring LATE-NC when they died in the 10th and 11th decades of their lives. Our study adds to the existing literature reporting seemingly protective effect of peri- and postmenopausal ERT against neurodegenerative dementia.

Characterizing Limbic-Predominant Age-Related TDP-43 Encephalopathy Without Alzheimer's Disease and Lewy Body Dementia in the Oldest Old: A Case Series.

BACKGROUND: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals. OBJECTIVE: Our aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer's disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART). METHODS: In 364 autopsies of the oldest old of The 90+ Study, we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART. RESULTS: Of 31% of participants who had LATE-NC, only 5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups. CONCLUSIONS: Despite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group.

Predicting the aggregation number of cationic surfactants based on ANN-QSAR modeling approaches: understanding the impact of molecular descriptors on aggregation numbers.

In this work, a quantitative structure-activity relationship (QSAR) study is performed on some cationic surfactants to evaluate the relationship between the molecular structures of the compounds with their aggregation numbers (AGGNs) in aqueous solution at 25 °C. An artificial neural network (ANN) model is combined with the QSAR study to predict the aggregation number of the surfactants. In the ANN analysis, four out of more than 3000 molecular descriptors were used as input variables, and the complete set of 41 cationic surfactants was randomly divided into a training set of 29, a test set of 6, and a validation set of 6 molecules. After that, a multiple linear regression (MLR) analysis was utilized to build a linear model using the same descriptors and the results were compared statistically with those of the ANN analysis. The square of the correlation coefficient (R 2) and root mean square error (RMSE) of the ANN and MLR models (for the whole data set) were 0.9392, 7.84, and 0.5010, 22.52, respectively. The results of the comparison revealed the efficiency of ANN in detecting a correlation between the molecular structure of surfactants and their AGGN values with a high predictive power due to the non-linearity in the studied data. Based on the ANN algorithm, the relative importance of the selected descriptors was computed and arranged in the following descending order: H-047 > ESpm12x > JGI6> Mor20p. Then, the QSAR data was interpreted and the impact of each descriptor on the AGGNs of the molecules were thoroughly discussed. The results showed there is a correlation between each selected descriptor and the AGGN values of the surfactants.

Modified Heider balance on Erdös-Rényi networks.

The lack of signed random networks in standard balance studies has prompted us to extend the Hamiltonian of the standard balance model. Random networks with tunable parameters are suitable for better understanding the behavior of standard balance as an underlying dynamics. Moreover, the standard balance model in its original form does not allow preserving tensed triads in the network. Therefore, the thermal behavior of the balance model has been investigated on a fully connected signed network recently. It has been shown that the model undergoes an abrupt phase transition with temperature. Considering these two issues, we examine the thermal behavior of the structural balance model defined on Erdös-Rényi random networks within the range of their connected regime. We provide a mean-field solution for the model. We observe a first-order phase transition with temperature for a wide range of connection probabilities. We detect two transition temperatures, T_{cold} and T_{hot}, characterizing a hysteresis loop. We find that with decreasing the connection probability, both T_{cold} and T_{hot} decrease. However, the slope of decreasing T_{hot} with decreasing connection probability is larger than the slope of decreasing T_{cold}. Hence, the hysteresis region gets narrower until it disappears in a certain connection probability. We provide a phase diagram in the temperature-tie density plane to accurately observe the metastable or coexistence region behavior. Then we justify our mean-field results with a series of Monte Carlo simulations.

Neuroimaging in the Oldest-Old: A Review of the Literature.

The oldest-old, those 85 years and older, are the fastest growing segment of the population and present with the highest prevalence of dementia. Given the importance of neuroimaging measures to understand aging and dementia, the objective of this study was to review neuroimaging studies performed in oldest-old participants. We used PubMed, Google Scholar, and Web of Science search engines to identify in vivo CT, MRI, and PET neuroimaging studies either performed in the oldest-old or that addressed the oldest-old as a distinct group in analyses. We identified 60 studies and summarized the main group characteristics and findings. Generally, oldest-old participants presented with greater atrophy compared to younger old participants, with most studies reporting a relatively stable constant decline in brain volumes over time. Oldest-old participants with greater global atrophy and atrophy in key brain structures such as the medial temporal lobe were more likely to have dementia or cognitive impairment. The oldest-old presented with a high burden of white matter lesions, which were associated with various lifestyle factors and some cognitive measures. Amyloid burden as assessed by PET, while high in the oldest-old compared to younger age groups, was still predictive of transition from normal to impaired cognition, especially when other adverse neuroimaging measures (atrophy and white matter lesions) were also present. While this review highlights past neuroimaging research in the oldest-old, it also highlights the dearth of studies in this important population. It is imperative to perform more neuroimaging studies in the oldest-old to better understand aging and dementia.

First permanent molars with accentuated line patterns: Assessment of childhood health in an urban complex of the fifth millennium before the present.

OBJECTIVES: The objectives are 1) to calculate the position of highly accentuated lines in dental enamel of a group of individuals from Shahr-i-Sokhta, a thriving urban centre in Bronze Age South West Asia; 2) to identify peak frequencies of physiologically stressful periods during early childhood of these individuals; and 3) to relate these peak frequencies to developmental milestones at population level. DESIGN: We analysed highly accentuated lines in the enamel of nine (n = 9) permanent mandibular first molars of nine individuals from the 5th millennium before the present urban and long-distance-trading complex, Shahr-i Sokhta (Iran). Age at death ranged between 4.5 years and 18-20 years. Permanent mandibular first molar enamel begins to mineralise before birth, and is normally completed sometime between 2.1-3.3 years, giving us insight to early childhood physiological stress, the ages at which it occurs, and any peaks in the frequencies in highly accentuated line formation, through histological sections investigated using transmitted light microscopy. RESULTS: Highly accentuated line peak frequencies occur in the sample at c. four, nine, eleven, and twelve months. After 1 year of age, no more peaks occur. CONCLUSION: The peak frequencies coincide with the timing timing of the type of developmental milestones which may have exposed the individuals to an increased pathogen load, injury, or sub-optimal diet. We note similarity in peak timings in the few published, disparate populations, suggest a potential link with attainment of developmental milestones connected with morbidity, and propose reporting standardised statistics to enable exploration of differences between populations in terms of postnatal health-related stress.

Education and Message Framing Increase Willingness to Undergo Research Lumbar Puncture: A Randomized Controlled Trial.

Reluctance to undergo lumbar puncture (LP) is a barrier to neurological disease biomarker research. We assessed whether an educational intervention increased willingness to consider research LP and whether message framing modified intervention effectiveness. We randomly assigned 851 recruitment registry enrollees who had previously indicated they were unwilling to be contacted about studies requiring LP to gain or loss framed video educational interventions describing the procedure and the probability of experiencing adverse events. The gain framed intervention emphasized the proportion of individuals free of adverse events; the loss frame emphasized the proportion experiencing adverse events. The primary outcome for the study was the participant's post-intervention agreement to be contacted about studies requiring LP. Participants were mean (SD) age 60.1 years (15.7), 69% female (n = 591), and mostly college educated and white. Among the 699 participants who completed the study, 43% (95% CI: 0.39, 0.47; n = 301) changed their response to agree to be contacted about studies requiring LP. We estimated that participants randomized to the gain framed intervention had 67% higher odds of changing their response compared to those randomized to the loss frame (Odds Ratio = 1.67; 95% CI: 1.24, 2.26; p < 0.001). A classification and regression tree model identified participants' pre-intervention willingness as the strongest predictor of changing response. Education, in particular education that alerts participants to the probability of not experiencing adverse events, may be an effective tool to increase participation rates in research requiring LP.