Frontal Cortex Lipid Alterations During the Onset of Alzheimer's Disease.

Background: Although sporadic Alzheimer's disease (AD) is a neurodegenerative disorder of unknown etiology, familial AD is associated with specific gene mutations. A commonality between these forms of AD is that both display multiple pathogenic events including cholinergic and lipid dysregulation. Objective: We aimed to identify the relevant lipids and the activity of their related receptors in the frontal cortex and correlating them with cognition during the progression of AD. Methods: MALDI-mass spectrometry imaging (MSI) and functional autoradiography was used to evaluate the distribution of phospholipids/sphingolipids and the activity of cannabinoid 1 (CB1), sphingosine 1-phosphate 1 (S1P1), and muscarinic M2/M4 receptors in the frontal cortex (FC) of people that come to autopsy with premortem clinical diagnosis of AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI). Results: MALDI-MSI revealed an increase in myelin-related lipids, such as diacylglycerol (DG) 36:1, DG 38:5, and phosphatidic acid (PA) 40:6 in the white matter (WM) in MCI compared to NCI, and a downregulation of WM phosphatidylinositol (PI) 38:4 and PI 38:5 levels in AD compared to NCI. Elevated levels of phosphatidylcholine (PC) 32:1, PC 34:0, and sphingomyelin 38:1 were observed in discrete lipid accumulations in the FC supragranular layers during disease progression. Muscarinic M2/M4 receptor activation in layers V-VI decreased in AD compared to MCI. CB1 receptor activity was upregulated in layers V-VI, while S1P1 was downregulated within WM in AD relative to NCI. Conclusions: FC WM lipidomic alterations are associated with myelin dyshomeostasis in prodromal AD, suggesting WM lipid maintenance as a potential therapeutic target for dementia.

Impact of incidental synucleinopathy in mild cognitive impairment due to Alzheimer disease.

Recent evidence suggests that the presence of α-synuclein Lewy bodies (LBs) correlates with accelerated disease progression in patients with Alzheimer disease (AD) but it is unclear whether this effect is also exerted in the mild cognitive impairment (MCI) phase of AD. We sought to determine whether incidental LB pathology in patients with MCI due to AD is associated with a faster rate of cognitive decline compared to MCI controls without LB pathology. We identified patients within the National Alzheimer's Coordinating Center (NACC) database with MCI due to AD and stratified the cohort by the presence or absence of synucleinopathy. We utilized a repeated measures longitudinal analysis of Mini-Mental State Examination (MMSE) scores to determine whether the decline in performance occurred at a greater rate in the synucleinopathy patients. A total of 206 participants were studied; 80 had coincident synucleinopathy. The rate of decline in MMSE scores between the groups did not differ. This may suggest that a synergistic effect of LB and AD neuropathology is only appreciable in the later stages of disease progression. Further investigation into the effect of mixed LB and AD pathology in the early stages of cognitive impairment is warranted to highlight opportunities for targeted early intervention in patients.

Meta-analysis of Montreal cognitive assessment diagnostic accuracy in amnestic mild cognitive impairment.

Background: The Montreal Cognitive Assessment (MoCA) is one of the most widely-used cognitive screening instruments and has been translated into several different languages and dialects. Although the original validation study suggested to use a cutoff of ≤26, subsequent studies have shown that lower cutoff values may yield fewer false-positive indications of cognitive impairment. The aim of this study was to summarize the diagnostic accuracy and mean difference of the MoCA when comparing cognitively unimpaired (CU) older adults to those with amnestic mild cognitive impairment (aMCI). Methods: PubMed and EMBASE databases were searched from inception to 22 February 2022. Meta-analyses for area under the curve (AUC) and standardized mean difference (SMD) values were performed. Results: Fifty-five observational studies that included 17,343 CU and 8,413 aMCI subjects were selected for inclusion. Thirty-nine studies were used in the AUC analysis while 44 were used in the SMD analysis. The overall AUC value was 0.84 (95% CI: 0.81, 0.87) indicating good diagnostic accuracy and a large effect size was noted for the SMD analysis (Hedge's g = 1.49, 95% CI: 1.33, 1.64). Both analyses had high levels of between-study heterogeneity. The median cutoff score for identifying aMCI was <24. Discussion and conclusion: The MoCA has good diagnostic accuracy for detecting aMCI across several different languages. The findings of this meta-analysis also support the use of 24 as the optimal cutoff when the MoCA is used to screen for suspected cognitive impairment.

Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial.

OBJECTIVE: This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS). METHODS: KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17ß-estradiol (Climara, 50 µg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits. RESULTS: Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17ß-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance. CONCLUSIONS: There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.

Protocol of the Berlin Long-term Observation of Vascular Events (BeLOVE): a prospective cohort study with deep phenotyping and long-term follow up of cardiovascular high-risk patients.

INTRODUCTION: The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations. METHODS AND ANALYSIS: A total of 8000 adult patients will be recruited who have either suffered an acute CV event (CVE) requiring hospitalisation or who have not experienced a recent acute CVE but are at high CV risk. An initial study examination is performed during the acute treatment phase of the index CVE or after inclusion into the chronic high risk arm. Deep phenotyping is then performed after ~90 days and includes assessments of the patient's medical history, health status and behaviour, cardiovascular, nutritional, metabolic, and anthropometric parameters, and patient-related outcome measures. Biospecimens are collected for analyses including 'OMICs' technologies (e.g., genomics, metabolomics, proteomics). Subcohorts undergo MRI of the brain, heart, lung and kidney, as well as more comprehensive metabolic, neurological and CV examinations. All participants are followed up for up to 10 years to assess clinical outcomes, primarily major adverse CVEs and patient-reported (value-based) outcomes. State-of-the-art clinical research methods, as well as emerging techniques from systems medicine and artificial intelligence, will be used to identify associations between patient characteristics, longitudinal changes and outcomes. ETHICS AND DISSEMINATION: The study was approved by the Charité-Universitätsmedizin Berlin ethics committee (EA1/066/17). The results of the study will be disseminated through international peer-reviewed publications and congress presentations. STUDY REGISTRATION: First study phase: Approved WHO primary register: German Clinical Trials Register: https://drks.de/search/de/trial/DRKS00016852; WHO International Clinical Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00016852. Recruitment started on July 18, 2017.Second study phase: Approved WHO primary register: German Clinical Trials Register DRKS00023323, date of registration: November 4, 2020, URL: http://www.drks.de/ DRKS00023323. Recruitment started on January 1, 2021.

Meta-Analysis of Animal Fluency Performance in Amnestic Mild Cognitive Impairment and Cognitively Unimpaired Older Adults.

Animal fluency is a commonly used neuropsychological measure that is used in the diagnosis of amnestic mild cognitive impairment (aMCI) and Alzheimer disease. Although most individuals with aMCI have clinically normal scores on this test, several studies have shown that aMCI individuals' performance is significantly lower than that of cognitively unimpaired (CU) individuals. The aim of this meta-analysis was to characterize the effect size of animal fluency performance differences between aMCI and CU individuals. Literature search with search terms used were: "animal fluency and mild cognitive impairment," "semantic fluency and mild cognitive impairment," "category fluency and mild cognitive impairment." Both the standardized mean difference and the raw mean difference were derived from random effects analyses. Demographically adjusted z-scores for animal fluency performance for the aMCI groups were obtained to determine normative performance. Nineteen studies were included in the analysis. The standardized mean difference for animal fluency performance between CU and aMCI was 0.89 (95% confidence interval: [0.73; 1.04], P <0.001), I2 =70.3% [52.7%; 81.4%], which reflects a large effect size with moderate heterogeneity. The raw mean difference was -4.08 [-4.75; -3.38], P <0.001. The mean animal fluency z-score for aMCI groups was in the Low Average range (z=-0.77). This study found a substantial difference in animal fluency performance between aMCI and CU individuals. The aMCI groups' normative performance did not fall into the impaired range, indicating that there are important subclinical differences in animal fluency performance that may inform the design of cognitive end points for Alzheimer's disease prevention trials.

γδ T cell-intrinsic IL-1R promotes survival during Staphylococcus aureus bacteremia.

Staphylococcus aureus is a leading cause of bacteremia, further complicated by the emergence of antibiotic-resistant strains such as methicillin-resistant S. aureus (MRSA). A better understanding of host defense mechanisms is needed for the development of host-directed therapies as an alternative approach to antibiotics. The levels of IL-1, IL-17, and TNF-α cytokines in circulation have been associated with predictive outcomes in patients with S. aureus bacteremia. However, their causative role in survival and the cell types involved in these responses during bacteremia is not entirely clear. Using a mouse model of S. aureus bacteremia, we demonstrated that IL-17A/F and TNF-α had no significant impact on survival, whereas IL-1R signaling was critical for survival during S. aureus bacteremia. Furthermore, we identified that T cells, but not neutrophils, monocytes/macrophages, or endothelial cells were the crucial cell type for IL-1R-mediated survival against S. aureus bacteremia. Finally, we determined that the expression of IL-1R on γδ T cell, but not CD4+ or CD8+ T cells was responsible for survival against the S. aureus bacteremia. Taken together, we uncovered a role for IL-1R, but not IL-17A/F and TNF-α in protection against S. aureus bacteremia. Importantly, γδ T cell-intrinsic expression of IL-1R was crucial for survival, but not on other immune cells or endothelial cells. These findings reveal potential cellular and immunological targets for host-directed therapies for improved outcomes against S. aureus bacteremia.

Neutrophil-intrinsic TNF receptor signaling orchestrates host defense against Staphylococcus aureus.

Staphylococcus aureus is the leading cause of skin and soft tissue infections and is a major health burden due to the emergence of antibiotic-resistant strains. To address the unmet need of alternative treatments to antibiotics, a better understanding of the protective immune mechanisms against S. aureus skin infection is warranted. Here, we report that tumor necrosis factor (TNF) promoted protection against S. aureus in the skin, which was mediated by bone marrow-derived immune cells. Furthermore, neutrophil-intrinsic TNF receptor (TNFR) signaling directed immunity against S. aureus skin infections. Mechanistically, TNFR1 promoted neutrophil recruitment to the skin, whereas TNFR2 prevented systemic bacterial dissemination and directed neutrophil antimicrobial functions. Treatment with a TNFR2 agonist showed therapeutic efficacy against S. aureus and Pseudomonas aeruginosa skin infections, which involved increased neutrophil extracellular trap formation. Our findings revealed nonredundant roles for TNFR1 and TNFR2 in neutrophils for immunity against S. aureus and can be therapeutically targeted for protection against bacterial skin infections.

Hypoxia-specific imaging in patients with lymphoma undergoing CAR-T therapy.

PURPOSE: Intratumoral hypoxia in non-Hodgkin's Lymphoma (NHL) may interfere with chimeric antigen receptor T-cell (CAR-T) function. We conducted a single-center pilot study (clinicaltrials.gov ID NCT04409314) of [18F]fluoroazomycin arabinoside, a hypoxia-specific radiotracer abbreviated as [18F]FAZA, to assess the feasibility of this positron emission tomography (PET) imaging modality in this population. METHODS: Patients with relapsed NHL being evaluated for CAR-T therapy received a one-time [18F]FAZA PET scan before pre-CAR-T lymphodepletion. A tumor to mediastinum (T/M) ratio of 1.2 or higher with regard to [18F]FAZA uptake was defined as positive for intratumoral hypoxia. We planned to enroll 30 patients with an interim futility analysis after 16 scans. RESULTS: Of 16 scanned patients, 3 had no evidence of disease by standard [18F]fluorodeoxyglucose PET imaging before CAR-T therapy. Six patients (38%) had any [18F]FAZA uptake above background. Using a T/M cutoff of 1.20, only one patient (a 68-year-old male with relapsed diffuse large B-cell lymphoma) demonstrated intratumoral hypoxia in an extranodal chest wall lesion (T/M 1.35). Interestingly, of all 16 scanned patients, he was the only patient with progressive disease within 1 month of CAR-T therapy. However, because of our low overall proportion of positive scans, our study was stopped for futility. CONCLUSIONS: Our pilot study identified low-level [18F]FAZA uptake in a small number of patients with NHL receiving CAR-T therapy. The only patient who met our pre-specified threshold for intratumoral hypoxia was also the only patient with early CAR-T failure. Future plans include exploration of [18F]FAZA in a more selected patient population.

Vesicular Glutamate Transporter Changes in the Cortical Default Mode Network During the Clinical and Pathological Progression of Alzheimer's Disease.

BACKGROUND: Altered glutamatergic neurotransmission may contribute to impaired default mode network (DMN) function in Alzheimer's disease (AD). Among the DMN hub regions, frontal cortex (FC) was suggested to undergo a glutamatergic plasticity response in prodromal AD, while the status of glutamatergic synapses in the precuneus (PreC) during clinical-neuropathological AD progression is not known. OBJECTIVE: To quantify vesicular glutamate transporter VGluT1- and VGluT2-containing synaptic terminals in PreC and FC across clinical stages of AD. METHODS: Unbiased sampling and quantitative confocal immunofluorescence of cortical VGluT1- and VGluT2-immunoreactive profiles and spinophilin-labeled dendritic spines were performed in cases with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or moderate-severe AD (sAD). RESULTS: In both regions, loss of VGluT1-positive profile density was seen in sAD compared to NCI, MCI, and mAD. VGluT1-positive profile intensity in PreC did not differ across groups, while in FC it was greater in MCI, mAD, and sAD compared to NCI. VGluT2 measures were stable in PreC while FC had greater VGluT2-positive profile density in MCI compared to sAD, but not NCI or mAD. Spinophilin measures in PreC were lower in mAD and sAD compared to NCI, while in FC they were stable across groups. Lower VGluT1 and spinophilin measures in PreC, but not FC, correlated with greater neuropathology. CONCLUSION: Frank loss of VGluT1 in advanced AD relative to NCI occurs in both DMN regions. In FC, an upregulation of VGluT1 protein content in remaining glutamatergic terminals may contribute to this region's plasticity response in AD.

Plasma NfL is associated with the APOE ε4 allele, brain imaging measurements of neurodegeneration, and lower recall memory scores in cognitively unimpaired late-middle-aged and older adults.

BACKGROUND: Plasma neurofilament light (NfL) is an indicator of neurodegeneration and/or neuroaxonal injury in persons with Alzheimer's disease (AD) and a wide range of other neurological disorders. Here, we characterized and compared plasma NfL concentrations in cognitively unimpaired (CU) late-middle-aged and older adults with two, one, or no copies of the APOE ε4 allele, the major genetic risk factor for AD. We then assessed plasma NfL associations with brain imaging measurements of AD-related neurodegeneration (hippocampal atrophy and a hypometabolic convergence index [HCI]), brain imaging measurements of amyloid-ß plaque burden, tau tangle burden and white matter hyperintensity volume (WMHV), and delayed and total recall memory scores. METHODS: Plasma NfL concentrations were measured in 543 CU 69 ± 9 year-old participants in the Arizona APOE Cohort Study, including 66 APOE ε4 homozygotes (HM), 165 heterozygotes (HT), and 312 non-carriers (NC). Robust regression models were used to characterize plasma NfL associations with APOE ε4 allelic dose before and after adjustment for age, sex, and education. They were also used to characterize plasma NfL associations with MRI-based hippocampal volume and WMHV measurements, an FDG PET-based HCI, mean cortical PiB PET measurements of amyloid-ß plaque burden and meta-region-of-interest (meta-ROI) flortaucipir PET measurements of tau tangle burden, and Auditory Verbal Learning Test (AVLT) Delayed and Total Recall Memory scores. RESULTS: After the adjustments noted above, plasma NfL levels were significantly greater in APOE ε4 homozygotes and heterozygotes than non-carriers and significantly associated with smaller hippocampal volumes (r = - 0.43), greater tangle burden in the entorhinal cortex and inferior temporal lobes (r = 0.49, r = 0.52, respectively), and lower delayed (r = - 0.27), and total (r = - 0.27) recall memory scores (p < 0.001). NfL levels were not significantly associated with PET measurements of amyloid-ß plaque or total tangle burden. CONCLUSIONS: Plasma NfL concentrations are associated with the APOE ε4 allele, brain imaging biomarkers of neurodegeneration, and less good recall memory in CU late-middle-aged and older adults, supporting its value as an indicator of neurodegeneration in the preclinical study of AD.

Oligomeric, phosphorylated, and truncated tau and spliceosome pathology within the entorhinal-hippocampal connectome across stages of Alzheimer's disease.

Neurofibrillary tangles (NFTs) contain abnormally phosphorylated tau proteins, which spread within components of the medial temporal lobe (MTL) memory circuit in Alzheimer's disease (AD). Here, we used quantitative immunohistochemistry to determine the density of posttranslational oligomeric (TOC1 and TNT1), phosphorylated (AT8), and late truncated (TauC3) tau epitopes within the MTL subfields including entorhinal cortex (EC) layer II, subiculum, Cornu Ammonis (CA) subfields, and dentate gyrus (DG) in subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. We also examined whether alterations of the nuclear alternative splicing protein, SRSF2, are associated with tau pathology. Although a significant increase in TOC1, TNT1, and AT8 neuron density occurred in the EC in MCI and AD, subicular, DG granule cell, and CA1 and CA3 densities were only significantly higher in AD. TauC3 counts were not different between connectome regions and clinical groups. SRSF2 intensity in AT8-positive cells decreased significantly in all regions independent of the clinical groups examined. CA1 and subicular AT8, TauC3, and oligomeric densities correlated across clinical groups. EC AT8 counts correlated with CA subfields and subicular and DG values across clinical groups. Oligomeric and AT8 CA1, EC, and subicular density correlated with Braak stage. Decreased nuclear SRSF2 in the presence of cytoplasmic phosphorylated tau suggests a dual-hit process in NFT formation within the entorhinal hippocampal connectome during the onset of AD. Although oligomeric and phosphorylated tau follow a stereotypical pattern, clinical disease stage determined density of tau deposition and not anatomic location within the entorhinal-hippocampal connectome.

Volumetric regional MRI and neuropsychological predictors of motor task variability in cognitively unimpaired, Mild Cognitive Impairment, and probable Alzheimer's disease older adults.

INTRODUCTION: The mechanisms linking motor function to Alzheimer's disease (AD) progression have not been well studied, despite evidence of AD pathology within motor brain regions. Thus, there is a need for new motor measure that is sensitive and specific to AD. METHODS: In a sample of 121 older adults (54 cognitive unimpaired [CU], 35 amnestic Mild Cognitive Impairment [aMCI], and 32 probable mild AD), intrasubject standard deviation (ISD) across six trials of a novel upper-extremity motor task was predicted with volumetric regional gray matter and neuropsychological scores using classification and regression tree (CART) analyses. RESULTS: Both gray matter and neuropsychological CART models indicated that motor task ISD (our measure of motor learning) was related to cortical regions and cognitive test scores associated with memory, executive function, and visuospatial skills. CART models also accurately distinguished motor task ISD of MCI and probable mild AD from CU. DISCUSSION: Variability in motor task performance across practice trials may be valuable for understanding preclinical and early-stage AD.

Meta-analysis of Controlled Oral Word Association Test (COWAT) FAS performance in amnestic mild cognitive impairment and cognitively unimpaired older adults.

Findings from several studies have shown that amnestic mild cognitive impairment (aMCI) older adults have significantly lower performance on phonemic fluency tasks relative to cognitively unimpaired (CU) older adults. These findings suggest that nonmemory domains, such as executive function, are impacted in aMCI. As Alzheimer's disease (AD) research has shifted toward identifying and characterizing preclinical AD, there is a need to identify subtle but significant cognitive changes that are below the threshold for clinical impairment. The aim of this meta-analysis was to examine phonemic fluency differences between aMCI and CU older adults. Data from 18 studies were included in this analysis that found that aMCI individuals' phonemic fluency performance was approximately seven points lower than CU individuals (Δ = -7.31, 95% CI [-9.10, -5.52], z = -8.01, p < 0.001), which represents a medium effect size of (g = 0.61, 95% CI [0.46, 0.76], z = 7.90, p < 0.001). Normative conversion of the aMCI groups' raw scores showed that all were in the normal range of performance. The findings of this meta-analysis demonstrate that significant subclinical deficits in phonemic fluency can be present in aMCI. This should prompt greater use of phonemic fluency tasks in outcome measures for observational and intervention studies.

A public resource of baseline data from the Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial.

INTRODUCTION: The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Trial evaluated the anti-oligomeric amyloid beta (Aß) antibody therapy crenezumab in cognitively unimpaired members of the Colombian presenilin 1 (PSEN1) E280A kindred. We report availability, methods employed to protect confidentiality and anonymity of participants, and process for requesting and accessing baseline data. METHODS: We developed mechanisms to share baseline data from the API ADAD Trial in consultation with experts and other groups sharing data from Alzheimer's disease (AD) prevention trials, balancing the need to protect anonymity and trial integrity with making data broadly available to accelerate progress in the field. We pressure-tested deliberate and inadvertent potential threats under specific assumptions, employed a system to suppress or mask both direct and indirect identifying variables, limited and firewalled data managers, and put forth specific principles requisite to receive data. RESULTS: Baseline demographic, PSEN1 E280A and apolipoprotein E genotypes, florbetapir and fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, clinical, and cognitive data can now be requested by interested researchers. DISCUSSION: Baseline data are publicly available; treatment data and biological samples, including baseline and treatment-related blood-based biomarker data will become available in accordance with our original trial agreement and subsequently developed Collaboration for Alzheimer's Prevention principles. Sharing of these data will allow exploration of important questions including the differential effects of initiating an investigational AD prevention therapy both before as well as after measurable Aß plaque deposition.

Application of robust regression in translational neuroscience studies with non-Gaussian outcome data.

Linear regression is one of the most used statistical techniques in neuroscience, including the study of the neuropathology of Alzheimer's disease (AD) dementia. However, the practical utility of this approach is often limited because dependent variables are often highly skewed and fail to meet the assumption of normality. Applying linear regression analyses to highly skewed datasets can generate imprecise results, which lead to erroneous estimates derived from statistical models. Furthermore, the presence of outliers can introduce unwanted bias, which affect estimates derived from linear regression models. Although a variety of data transformations can be utilized to mitigate these problems, these approaches are also associated with various caveats. By contrast, a robust regression approach does not impose distributional assumptions on data allowing for results to be interpreted in a similar manner to that derived using a linear regression analysis. Here, we demonstrate the utility of applying robust regression to the analysis of data derived from studies of human brain neurodegeneration where the error distribution of a dependent variable does not meet the assumption of normality. We show that the application of a robust regression approach to two independent published human clinical neuropathologic data sets provides reliable estimates of associations. We also demonstrate that results from a linear regression analysis can be biased if the dependent variable is significantly skewed, further indicating robust regression as a suitable alternate approach.

Neuropathologic validation of the Alzheimer's Questionnaire.

The Alzheimer's Questionnaire (AQ) is an informant-based screening tool with good diagnostic accuracy for Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). The aim of this study is to validate the AQ with AD-associated neuritic plaque (NP) and neurofibrillary tangle (NFT) pathology. Data from 205 prospectively followed autopsy cases clinically classified as AD (n = 90), aMCI (n = 42), or cognitively unimpaired (CU, n = 73) were used. Semi-quantitative measures of NP and NFT pathology were correlated with the AQ, Clinical Dementia Rating Sum of Boxes (CDR-SOB), and the Mini-Mental State Exam (MMSE). The AQ correlated significantly (p < 0.001) with NP load (r = 0.37) and NFT load (r = 0.57). The MMSE and CDR-SOB showed similar correlations with NP load (r = - 0.37, r = 0.35, respectively) and NFT load (r = - 0.58, r = 0.55, respectively). The AQ correlates well with NP and NFT pathology of AD, which provides additional confidence to clinicians using the AQ to screen for AD-related cognitive impairment.

User Perceptions and Needs Analysis of a Virtual Coach for Active and Healthy Ageing-An International Qualitative Study.

Virtual coaching systems show great potential for meeting the challenges of demographic change. However, the proportion of older users in the field of digital technologies is far behind that of younger people. As part of the e-VITA project, semi-structured interviews were conducted in Japan, France, Italy and Germany with 58 people aged 65 and over, and the content was analyzed with the aim of obtaining information about how older adults organize their everyday lives, also with regard to the COVID-19 pandemic, how they deal with their health, what role digital technologies play in the lives of the interviewees and why they oppose progressive digitization. Second, the survey asked why the older adults oppose a virtual coach, which is to be developed in the e-VITA project to support older adults in healthy and active aging, and what barriers they see in a possible implementation. It was found that older respondents lead active, varied lives and that the COVID-19 pandemic contributed to the increased use of digital solutions. In addition, respondents were consciously addressing their own health. With regard to a virtual coach, barriers were seen primarily in the area of data security and sharing. It can be concluded from this that heterogeneity among older user groups should be taken into account when developing virtual coaches. In addition, aspects of data security and data protection should be presented in a clearly understandable and transparent manner.

Neurogenesis and neuronal differentiation in the postnatal frontal cortex in Down syndrome.

Although Down syndrome (DS), the most common developmental genetic cause of intellectual disability, displays proliferation and migration deficits in the prenatal frontal cortex (FC), a knowledge gap exists on the effects of trisomy 21 upon postnatal cortical development. Here, we examined cortical neurogenesis and differentiation in the FC supragranular (SG, II/III) and infragranular (IG, V/VI) layers applying antibodies to doublecortin (DCX), non-phosphorylated heavy-molecular neurofilament protein (NHF, SMI-32), calbindin D-28K (Calb), calretinin (Calr), and parvalbumin (Parv), as well as ß-amyloid (APP/Aß and Aß1-42) and phospho-tau (CP13 and PHF-1) in autopsy tissue from age-matched DS and neurotypical (NTD) subjects ranging from 28-weeks (wk)-gestation to 3 years of age. Thionin, which stains Nissl substance, revealed disorganized cortical cellular lamination including a delayed appearance of pyramidal cells until 44 wk of age in DS compared to 28 wk in NTD. SG and IG DCX-immunoreactive (-ir) cells were only visualized in the youngest cases until 83 wk in NTD and 57 wk DS. Strong SMI-32 immunoreactivity was observed in layers III and V pyramidal cells in the oldest NTD and DS cases with few appearing as early as 28 wk of age in layer V in NTD. Small Calb-ir interneurons were seen in younger NTD and DS cases compared to Calb-ir pyramidal cells in older subjects. Overall, a greater number of Calb-ir cells were detected in NTD, however, the number of Calr-ir cells were comparable between groups. Diffuse APP/Aß immunoreactivity was found at all ages in both groups. Few young cases from both groups presented non-neuronal granular CP13 immunoreactivity in layer I. Stronger correlations between brain weight, age, thionin, DCX, and SMI-32 counts were found in NTD. These findings suggest that trisomy 21 affects postnatal FC lamination, neuronal migration/neurogenesis and differentiation of projection neurons and interneurons that likely contribute to cognitive impairment in DS.

Patient-Centered Outcomes in a Randomized Trial Investigating a Multimodal Prevention Program After Transient Ischemic Attack or Minor Stroke: The INSPiRE-TMS Trial.

BACKGROUND: The INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) investigated effects of a multicomponent support program in patients with nondisabling stroke or transient ischemic attack. Although secondary prevention targets were achieved more frequently in the intensified care group, no significant differences were seen in rates of recurrent major vascular events. Here, we present the effects on prespecified patient-centered outcomes. METHODS: In a multicenter trial, we randomized patients with modifiable risk factors either to the intensified or conventional care alone program. Intensified care was provided by stroke specialists and used feedback and motivational interviewing strategies (≥8 outpatient visits over 2 years) aiming to improve adherence to secondary prevention targets. We measured physical fitness, disability, cognitive function and health-related quality of life by stair-climbing test, modified Rankin Scale, Montreal Cognitive Assessment, and European Quality of Life 5 Dimension 3 Level during the first 3 years of follow-up. RESULTS: Of 2072 patients (mean age: 67.4years, 34% female) assessed for the primary outcome, patient-centered outcomes were collected in 1,771 patients (877 intensified versus 894 conventional care group). Physical fitness improved more in the intensified care group (mean between-group difference in power (Watt): 24.5 after 1 year (95% CI, 5.5-43.5); 36.1 after 2 years (95% CI, 13.1-59.7) and 29.6 (95% CI, 2.0-57.3 after 3 years). At 1 year, there was a significant shift in ordinal regression analysis of modified Rankin Scale in favor of the intensified care group (common odds ratio, 1.23 [95% CI, 1.03-1.47]) but not after 2 (odds ratio, 1.17 [95% CI, 0.96-1.41]) or 3 years (odds ratio, 1.16 [95% CI, 0.95-1.43]) of follow-up. However, Montreal Cognitive Assessment and European Quality of Life 5 Dimension scores showed no improvement in the intensified intervention arm after 1, 2, or 3 years of follow-up. CONCLUSIONS: Patients of the intensified care program group had slightly better results for physical fitness and modified Rankin Scale after 1 year, but none of the other patient-centered outcomes was significantly improved. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01586702.