Pathological and neurophysiological outcomes of seeding human-derived tau pathology in the APP-KI NL-G-F and NL-NL mouse models of Alzheimer's Disease.

The two main histopathological hallmarks that characterize Alzheimer's Disease are the presence of amyloid plaques and neurofibrillary tangles. One of the current approaches to studying the consequences of amyloid pathology relies on the usage of transgenic animal models that incorporate the mutant humanized form of the amyloid precursor protein (hAPP), with animal models progressively developing amyloid pathology as they age. However, these mice models generally overexpress the hAPP protein to facilitate the development of amyloid pathology, which has been suggested to elicit pathological and neuropathological changes unrelated to amyloid pathology. In this current study, we characterized APP knock-in (APP-KI) animals, that do not overexpress hAPP but still develop amyloid pathology to understand the influence of protein overexpression. We also induced tau pathology via human-derived tau seeding material to understand the neurophysiological effects of amyloid and tau pathology. We report that tau-seeded APP-KI animals progressively develop tau pathology, exacerbated by the presence of amyloid pathology. Interestingly, older amyloid-bearing, tau-seeded animals exhibited more amyloid pathology in the entorhinal area, isocortex and hippocampus, but not thalamus, which appeared to correlate with impairments in gamma oscillations before seeding. Tau-seeded animals also featured immediate deficits in power spectra values and phase-amplitude indices in the hippocampus after seeding, with gamma power spectra deficits persisting in younger animals. Both deficits in hippocampal phase-amplitude coupling and gamma power differentiate tau-seeded, amyloid-positive animals from buffer controls. Based on our results, impairments in gamma oscillations appear to be strongly associated with the presence and development of amyloid and tau pathology, and may also be an indicator of neuropathology, network dysfunction, and even potential disposition to the future development of amyloid pathology.

Neurophysiological effects of human-derived pathological tau conformers in the APPKM670/671NL.PS1/L166P amyloid mouse model of Alzheimer's disease.

Alzheimer's Disease (AD) is a neurodegenerative disease characterized by two main pathological hallmarks: amyloid plaques and intracellular tau neurofibrillary tangles. However, a majority of studies focus on the individual pathologies and seldom on the interaction between the two pathologies. Herein, we present the longitudinal neuropathological and neurophysiological effects of a combined amyloid-tau model by hippocampal seeding of human-derived tau pathology in the APP.PS1/L166P amyloid animal model. We statistically assessed both neurophysiological and pathological changes using linear mixed modelling to determine if factors such as the age at which animals were seeded, genotype, seeding or buffer, brain region where pathology was quantified, and time-post injection differentially affect these outcomes. We report that AT8-positive tau pathology progressively develops and is facilitated by the amount of amyloid pathology present at the time of injection. The amount of AT8-positive tau pathology was influenced by the interaction of age at which the animal was injected, genotype, and time after injection. Baseline pathology-related power spectra and Higuchi Fractal Dimension (HFD) score alterations were noted in APP.PS1/L166P before any manipulations were performed, indicating a baseline difference associated with genotype. We also report immediate localized hippocampal dysfunction in the electroencephalography (EEG) power spectra associated with tau seeding which returned to comparable levels at 1 month-post-injection. Longitudinal effects of seeding indicated that tau-seeded wild-type mice showed an increase in gamma power earlier than buffer control comparisons which was influenced by the age at which the animal was injected. A reduction of hippocampal broadband power spectra was noted in tau-seeded wild-type mice, but absent in APP.PS1 animals. HFD scores appeared to detect subtle effects associated with tau seeding in APP.PS1 animals, which was differentially influenced by genotype. Notably, while tau histopathological changes were present, a lack of overt longitudinal electrophysiological alterations was noted, particularly in APP.PS1 animals that feature both pathologies after seeding, reiterating and underscoring the difficulty and complexity associated with elucidating physiologically relevant and translatable biomarkers of Alzheimer's Disease at the early stages of the disease.

School Achievement in Early Adolescence Is Associated With Students' Self-Perceived Executive Functions.

The primary aim of this study was to investigate the relation between self-perceived executive functions (EFs) and the school achievement of young adolescents (aged 10-12 years), while controlling for parental education and sex. We specifically focused on executive aspects of daily life behavior and the higher-order EFs, as measured with self-report, rather than on the more basic EFs which have been the primary focus of prior investigations. In two independent samples of sixth graders (N > 200 each), students evaluated their EFs on a self-report questionnaire, the Amsterdam Executive Functioning Inventory. School achievement in the domains of mathematics and reading comprehension were evaluated with nationally used, norm-based achievement tests. Results revealed that the self-perceived EFs of young adolescents were significantly correlated with their school achievement in both study samples. School achievement was also correlated with the level of parental education, but the factor sex did not have such influence. In study 1, self-perceived EFs explained additional variance in school achievement, while controlling for parental education and sex. In study 2, this was only the case for the most robust measure of school achievement, i.e., the end-of-primary-school final achievement test. Furthermore, besides the relation with achievement tests, we also found a relation between self-perceived EFs and teacher ratings behavioral problems in the classroom. Together, our findings imply that young students can properly reflect on the effectiveness and appropriateness of their EFs in a way that is relevant to their academic achievement and classroom behavior. The findings underscore the importance of considering the development of EFs and parental education in the evaluation of academic achievements in early adolescence.

The letter digit substitution test: demographic influences and regression-based normative data for school-aged children.

The Letter Digit Substitution Test (LDST) was administered to a sample of N=296 healthy children (aged between 8.03 and 15.87). The aim of the present study was to evaluate the impact of age, gender, and parental educational level on LDST performance and to establish demographically corrected normative data. The results showed that the relationship between age and LDST performance was curvilinear (i.e., improvements in test performance were more pronounced for younger children than for older children) and was moderated by gender (i.e., the gender differences were small at younger ages but increased as a function of age, with girls outperforming boys). Moreover, children who had parents with a higher level of education outperformed their counterparts who had parents with a lower level of education. Regression-based normative LDST data were established, and an automatic scoring program was provided.

[Category fluency (animals, professions) in normal cognitive ageing and dementia]. / Klinische bruikbaarheid van categoriegebonden woordproductie voor het onderscheiden van dementie en normale cognitieve veroudering.

Regression-based normative data for commonly used semantic verbal fluency test (VFT) scores were derived from data of the Maastricht Aging Study (N=1,825; age range 24-81). Animal naming, profession naming, and the summed score (animal + profession naming) were shown to be profoundly affected by demographical variables, especially age and educational level. The clinical utility of the newly established regression-based VFT norms was evaluated in a large sample of psychogeriatric patients (N=1,063, of which n=890 met the criteria for Alzheimer's or vascular dementia). Results showed that the animal naming VFT score was the most sensitive measure to distinguish normal aging from dementia (when the specificities of the various VFT measures were equated). Fifty patients were found to commit stuck-in-set perseverations, i.e. they generated animal names during test administration of the profession naming VFT. The prevalence of stuck-in-set perseveration was 11.3% in Parkinson dementia and frontal variant frontotemporal dementia, versus 4.6% and 5.3% in dementia of the Alzheimer type and vascular dementia, respectively. Bivariate analyses revealed that people who committed stuck-in-set perseverations were more deficient on a measure of free recall and on several tests of executive control, such as the Expanded Mental Control Test, the Behavioral Dyscontrol Scale and the Alternating Graphical Sequences Test as a measure of response inhibition. Using multivariate logistic regression analysis, only the Alternating Graphical Sequences Test retained an independent effect in the association with stuck-in-set perseveration.

Klinische bruikbaarheid van categoriegebonden woordproductie voor het onderscheiden van dementie en normale cognitieve veroudering.

CATEGORY FLUENCY (ANIMALS, PROFESSIONS) IN NORMAL COGNITIVE AGEING AND DEMENTIA: Regression-based normative data for commonly used semantic verbal fluency test (VFT) scores were derived from data of the Maastricht Aging Study (N=1,825; age range 24-81). Animal naming, profession naming, and the summed score (animal + profession naming) were shown to be profoundly affected by demographical variables, especially age and educational level. The clinical utility of the newly established regression-based VFT norms was evaluated in a large sample of psychogeriatric patients (N=1,063, of which n=890 met the criteria for Alzheimer's or vascular dementia). Results showed that the animal naming VFT score was the most sensitive measure to distinguish normal aging from dementia (when the specificities of the various VFT measures were equated). Fifty patients were found to commit stuck-in-set perseverations, i.e. they generated animal names during test administration of the profession naming VFT. The prevalence of stuck-in-set perseveration was 11.3% in Parkinson dementia and frontal variant frontotemporal dementia, versus 4.6% and 5.3% in dementia of the Alzheimer type and vascular dementia, respectively. Bivariate analyses revealed that people who committed stuck-in-set perseverations were more deficient on a measure of free recall and on several tests of executive control, such as the Expanded Mental Control Test, the Behavioral Dyscontrol Scale and the Alternating Graphical Sequences Test as a measure of response inhibition. Using multivariate logistic regression analysis, only the Alternating Graphical Sequences Test retained an independent effect in the association with stuck-in-set perseveration.