Classical AD Research Articles

Differences in the Distribution of Aβ in the Brain between U.S. Veterans and Adults aged 62+ and suffering from Alzheimer's Disease.

Elevated concentration of amyloids in the cerebrum results in elevated risks for cerebral hemorrhage and early AD onset following early depression/dementia onset. In this study, we compare patterns of amyloid depositions across eight regions of interest of the human brain between U.S. Veterans and non-Veterans adults aged 62+. Data were taken from the ADNI and DoD-ADNI studies. A pseudo-randomization algorithm was applied to achieve comparability, reduce bias due to age mismatching, and account for non-treatment-related differences between subsamples extracted from DoD-ADNI and ADNI databases. The pool of participants included data about age, race, apolipoprotein ε4 allele (APOE) status, modified Hachinski Ischemic Score, education level, and geriatric depression score, which were used to build a propensity score. Aβ concentration, resulting from the PET image analysis, in key brain regions of interest, and two categorical variables describing the 0.79 and 1.11 cutoffs were used as outcomes, while the Veteran and AD status were used as predictors. To balance subsamples, we applied a pseudo-randomization algorithm, eliminating the observed sources of heterogeneity. We used a generalized linear model for continuous variables and the logistic regression model for binary variables. The pattern of the Aβ distribution in Veteran's brains was found to be different from the classic AD pattern. The amyloid depositions following Veteran status were concentrated in cerebellar gray matter and the cerebellum in general. In contrast, the AD pattern shows more Aβ depositions in the frontal lobe, cingulate cortex, parietal, and temporal lobes, along with higher whole-cerebrum concentration of amyloids. Since Florbetapir PET cannot distinguish between senile plaques and depositions in blood vessels, the elevated concentration of amyloids in a cerebellum for participants with the Veteran status may suppose elevated risks for cerebral hemorrhage and early AD onset following early depression/dementia onset.

Blood‐based biomarkers for Alzheimer’s Disease in Down Syndrome

AbstractBackgroundPeople with DS are at high risk to develop Alzheimer’s disease dementia (AD) (Lott & Head, 2001). Predicting and monitoring decline and onset of dementia is a diagnostic challenge and of essence in daily care and support for people with DS. Behavioral and Psychological Symptoms of Dementia (BPSD) are an easily accessible tool for the prediction of dementia onset in the DS population. The BPSD‐DS II scale was developed and validated by our team to identify behavioral changes linked to AD between the last six months and pre‐existing behavior in an individual with DS (Dekker et al., 2021). This project is based on a cohort of DS individuals without AD (n = 94), with AD (n = 43), or with questionable AD (qAD) (n = 54) aged >35 years. At inclusion, the BPSD‐DS II was applied to assess AD‐linked behavioral changes, and biofluid sampling was performed as well. Changes in cerebrospinal fluid (CSF) levels of monoaminergic neurotransmitters and metabolites have been associated with BPSD in AD (Dekker et al., 2015). However, CSF sampling procedures remain difficult in DS, illustrating the need for blood biomarkers. BPSD‐DS II results will be correlated with the serum levels of monoaminergic and classical AD biomarkers. Three years post‐inclusion, a follow‐up study was conducted to assess the evolution of possible AD dementia within this group and to determine the predictive values of the BPSD‐DS II scale and the different analytes.MethodWe will use reversed‐phase ultra‐high performance liquid chromatography with electrochemical detection to determine the levels of (nor)epinephrine, dopamine, serotonin and their metabolic products in serum. We will use the Simoaâ platform on the serum of clients with DS without or with (q)AD to detect the levels of Ab40, Ab42, total tau, phosphorylated tau, Glial Fibrillary Acidic Protein and Neurofilament Light chain.ResultWe expect a correlation between the results of the BPSD‐DS II and the levels of the monoamines and classical biomarkers in patients with DS without or with (q)AD.ConclusionThe diagnosis predicted by the results of the BPSD‐DS II correlates with the levels of monoamines and classical biomarkers in individuals with DS without or with (q)AD.

Young-onset Alzheimer’s dementia mimicking progressive myoclonic epilepsy spectrum

BackgroundYoung-onset Alzheimer’s dementia (YOAD) refers to the onset of disease before the age of 40 years. Classical AD typically presents with memory impairment with involvement of other cognitive domains like language, visuospatial orientation. On contrary, YOAD shows phenotypic heterogeneity in the form of predominant psychiatric disturbances apart from dementia and rarely seizures, cerebellar ataxia. We report a 36-year-old lady with dementia, myoclonus, seizures and cerebellar ataxia of 3 year duration mimicking progressive myoclonic epilepsy (PME) spectrum who had novel missense mutation in PSEN1 gene (L226F) suggestive of YOAD.Case presentationA 36-year-old lady presented with seizures in the form of generalized tonic–clonic seizures of 3 year duration followed by multifocal myoclonic jerks, cognitive decline of 2 year duration and imbalance while walking of 1 year duration. Montreal cognitive assessment (MOCA) score was 6/30. Addenbrooke’s cognitive examination III (ACE-III) score was 16/100. The mental status examination showed diffuse impairment of lobar functions. Brain magnetic resonance imaging showed diffuse cerebral and cerebellar atrophy. Skin biopsy did not show Lafora bodies or dermal inclusions on electron microscopy. Whole exome sequencing showed pathogenic missense variant NM_000021.4(PSEN1):c.676C > T (p.Leu226Phe) in PSEN1 gene suggestive of YOAD.ConclusionsYOAD due to PSEN1 mutation has to be considered in patients with cerebellar ataxia, seizures, myoclonus, dementia with psychiatric disturbances. This case highlights the high index of suspicion for differential diagnosis of YOAD in patients with young-onset dementia with ataxia, seizures and myoclonus.

Retinal Alterations as Potential Biomarkers of Structural Brain Changes in Alzheimer’s Disease Spectrum Patients

Retinal imaging being a potential biomarker for Alzheimer's disease is gradually attracting the attention of researchers. However, the association between retinal parameters and AD neuroimaging biomarkers, particularly structural changes, is still unclear. In this cross-sectional study, we recruited 25 cognitively impaired (CI) and 21 cognitively normal (CN) individuals. All subjects underwent retinal layer thickness and microvascular measurements with optical coherence tomography angiography (OCTA). Gray matter and white matter (WM) data such as T1-weighted magnetic resonance imaging and diffusion tensor imaging, respectively, were also collected. In addition, hippocampal subfield volumes and WM tract microstructural alterations were investigated as classical AD neuroimaging biomarkers. The microvascular and retinal features and their correlation with brain structural imaging markers were further analyzed. We observed a reduction in vessel density (VD) at the inferior outer (IO) sector (p = 0.049), atrophy in hippocampal subfield volumes, such as the subiculum (p = 0.012), presubiculum (p = 0.015), molecular_layer_HP (p = 0.033), GC-ML-DG (p = 0.043) and whole hippocampus (p = 0.033) in CI patients. Altered microstructural integrity of WM tracts in CI patients was also discovered in the cingulum hippocampal part (CgH). Importantly, we detected significant associations between retinal VD and gray matter volumes of the hippocampal subfield in CI patients. These findings suggested that the retinal microvascular measures acquired by OCTA may be markers for the early prediction of AD-related structural brain changes.

JT gravity from partial reduction and defect extremal surface

We propose the three-dimensional counterpart for Jackiw-Teitelboim gravity coupled with CFT2 bath based on partial reduction. The three-dimensional counterpart is classical AdS gravity with a defect brane which has small fluctuation in transverse direction. We derive full Jackiw-Teitelboim gravity action by considering the transverse fluctuation as a dilaton field. We demonstrate that the fine-grained entropy computed from island formula precisely agrees with that computed from defect extremal surface. Our construction provides a Lorentzian higher dimensional counterpart for Jackiw-Teitelboim gravity glued to a bath and therefore offers a framework to study problems such as black hole information paradox.

Development of an Inducible, Replication-Competent Assay Cell Line for Titration of Infectious Recombinant Adeno-Associated Virus Vectors.

An important quality attribute of a recombinant adeno-associated virus (rAAV) as a therapeutic vector is its infectivity. Current assays to quantify infectious rAAV rely on coinfection with a helper virus such as adenovirus (Ad), which requires helper virus preparation and introduces additional variability. A simple method that has high sensitivity and removes the need for helper virus would improve assay consistency and facilitate high-throughput applications such as rAAV producer cell line development. In this study, we describe a stable assay cell line that was generated by integrating the coding sequences for AAV Rep68 and Ad E4orf6 and DNA binding protein under the control of inducible promoters. The Rep68 protein expression was further modulated by a ligand-responsive destabilization domain. In several benchmarks, the cell line gave comparable titers with those obtained using a classical Ad coinfection method. The cell line was also used to titer vectors of multiple rAAV serotypes. This cell line has the potential to serve as an effective and robust tool for quantifying infectious rAAV titers to advance gene therapy vector biomanufacturing.

Comments on classical AdS flux vacua with scale separation

AdS flux vacua with a parametric separation between the AdS and KK scales have been conjectured to be in the Swampland. We study flux compactifications of massive IIA supergravity with O6 planes which are claimed to allow moduli-stabilised and scale separated AdS3 and AdS4 vacua at arbitrary weak coupling and large volume. A recent refinement of the AdS Distance Conjecture is shown to be inconsistent with this class of AdS3 vacua because the requisite discrete higher form symmetries are absent. We further perform a tree-level study of non-perturbative decays for the nonsupersymmetric versions of the AdS3 solutions, and find that the vacua are stable within this approximation. Finally, we provide an initial investigation of the would-be dual CFT2s and CFT3s. We study roughly a dozen different models and find for all AdS4 DGKT-type vacua that the dual operators to the lightest scalars have integer dimensions. For the putative CFT2 dual theories of the AdS3 vacua we find no integer dimensions for the operators.

A panel of novel astrocytic and synaptic biomarkers in serum and CSF for the differential diagnosis of frontotemporal dementia

AbstractBackgroundFrontotemporal dementia (FTD) is the second most common form of presenile dementia. The differential diagnosis of FTD is still a challenging task due to its symptomatic overlap with other neurological diseases and the lack of diagnostic biomarkers. Here, we aimed to investigate the diagnostic potential of novel biomarkers in cerebrospinal fluid (CSF) and blood.MethodWe included 137 patients from the Centre for Memory Disturbances in Perugia with a diagnosis of FTD (n=37), Alzheimer’s disease (AD, n=47), Parkinson’s Disease (PD, n=14), Dementia with Lewy bodies (DLB, n=8), and cognitively unimpaired patients with other neurological diseases as controls (OND, n=31). All had AD biomarker measurements available. Enzyme‐linked immunosorbent assay (ELISA) or single molecule array (Simoa) were used to quantify the biomarker levels of NPTX2, NPTXR, NfL and GFAP in CSF, as well as NfL and GFAP in serum. Statistical analyses were performed using age and sex corrected analysis of covariance (ANCOVA), generalized linear mixed models (GLMM), ROC analyses, and Spearman correlation coefficients (ρ).ResultDifferences in protein levels across diagnostic groups were found for NPTX2, NPTXR, NfL (serum and CSF), and GFAP (serum and CSF, figure 1). GLMM predicted NPTX2 and total tau (t‐tau) to best distinguish FTD from OND (p<0.002), while serum GFAP and t‐tau best distinguished FTD from AD (p<0.05). A combined panel of NPTX2, serum GFAP and t‐tau differentiated FTD from the other groups with good accuracy (table 1). Serum GFAP and NPTX2 correlated negatively in FTD (ρ =‐0.40, p<0.05) and AD (ρ=‐0.31, p<0.05), but positively in DLB (ρ =0.87, p<0.01), while no significant correlation was found in OND and PD (figure 2).ConclusionWe show the potential use of a novel biomarker panel including CSF t‐tau, CSF NPTX2 and serum GFAP, for differential diagnosis of FTD from other dementias. The included biomarkers reflect different neurological pathways, i.e. neurodegeneration, synaptic and astrocytic function, respectively. This suggests a unique interplay of these pathways in FTD and demonstrates the added value of the novel biomarkers to the established classical AD biomarkers. To assess the diagnostic potential of this novel panel, validation in a larger cohort should be performed.

ADAM10 plasma levels predict worsening in cognition of older adults: a 3-year follow-up study

BackgroundBlood-based biomarkers for Alzheimer’s disease (AD) are highly needed in clinic practice. So far, the gold standards for AD diagnosis are brain neuroimaging and beta-amyloid peptide, total tau, and phosphorylated tau in cerebrospinal fluid (CSF); however, they are not attractive for large-scale screening. Blood-based biomarkers allow an initial large-scale screening of patients under suspicion that could later be tested for the already established CSF biomarkers. To this regard, in this study, we evaluated whether plasma ADAM10 levels would be predictors of declines in cognition in community-dwelling older adults after a 3-year period follow-up.MethodsThis was a 3-year longitudinal cohort study that included 219 community-dwelling older adults. Sociodemographic, clinical, lifestyle, depressive symptoms (GDS), and cognitive data (Mini-Mental State Examination, MMSE; Clock Drawing test, CDT) were gathered. The measurement of ADAM10 plasma levels was performed using a sandwich ELISA kit. Bivariate comparisons between groups were performed using Wilcoxon-Mann-Whitney for continuous data and Pearson’s chi-square tests with Yates continuity correction for categorical data. Longitudinal analyzes of changes in the MMSE scores were performed using linear mixed-effects modeling.ResultsBaseline MMSE scores and ADAM10 levels were significantly associated with MMSE scores on the follow-up assessment. When analyzing the interaction with time, normal MMSE scores and the ADAM10 plasma levels at baseline presented a significant and independent negative association with MMSE score values on the follow-up assessment. The analyses also showed that the predictive effect of ADAM10 plasma levels on decreasing MMSE scores on follow-up seems to be more pronounced in participants with normal MMSE, when compared with those with altered MMSE scores at baseline.ConclusionsConsidering that ADAM10 increase in plasma is detected as soon as in mild cognitive impairment (MCI) patients, the results presented here may support the complementary clinical use of this biomarker, in addition to the classical AD biomarkers. Taken together, these results provide the first direct evidence that changes in ADAM10 plasma levels are predictors of cognitive worsening in older adults. Moreover, this work can shed light on the study of blood biomarkers for AD and contribute to the advancement of the area.

The cerebrospinal fluid fractalkine as a biomarker in mild cognitive impairment (MCI)

AbstractBackgroundMild cognitive impairment (MCI) is a neurological disorder that occurs in older adults and could be a very early phase of AD dementia. It is not only medical but also socioeconomic and legal problem. Since the MCI symptoms are not yet associated with such serious memory problems as in dementia, it may be difficult to assess the patient's legal capacity. This is an extremely important issue, among others, from the point of view of the patient's decision about his/her treatment process. His ability to fully understand his health situation and the ability to make rational decisions, including being aware of its effects, can be difficult to assess, which has significant legal effects. Therefore, the biomarkers of early stage of dementia are critically important. Growing body of evidence indicated that overexpression of CX3CL‐1 may influence on tau pathology and modulate the dementia disorders development. In our investigation we aim to measure the cerebrospinal fluid concentration of fractalkine to assess the potential usefulness of this protein in the diagnosis of MCI patients. Moreover, the CSF CX3CL‐1 level was compared to the concentrations of classical AD biomarkers, including Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181.MethodThe study included 18 patients with MCI and 18 non‐demented controls. The cerebrospinal fluid levels of CX3CL‐1 and classical AD biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181, were assessed by immunoenzyme assays.ResultThe concentration of fractalkine was significantly higher in cerebrospinal fluid of MCI patients when compared to non‐demented controls. The increased CSF levels of CX3CL‐1 were observed to significantly correlate with amyloid beta 1‐42 (Aβ‐42) and phosphorylated tau protein (pTau181) in mild cognitive impairment MCI subjects. Moreover, similar association between CX3CL‐1 concentrations and Aβ‐42/Aβ‐40 ratio was revealed in the control group.ConclusionPresented findings indicate a potential role of CX3CL‐1 in the pathology of MCI and possible usefulness of this protein in the early diagnosis of patients with cognitive impairment. The study was conducted with the use of equipment purchased by Medical University of Białystok as part of the RPOWP 2007‐2013 funding, Priority I, Axis 1.1, contract No. UDA‐RPPD.01.01.00‐20‐001/15‐00 dated 26.06.2015.

Cerebrospinal Fluid and Blood CX3CL1 as a Potential Biomarker in Early Diagnosis and Prognosis of Dementia.

A growing body of evidence highlights the crucial role of neuroinflammation and chemokine involvement in cognitive impairment pathophysiology. Fractalkine (CX3CL1) appears to be a relevant causative factor in the development of dementia, particularly at the early stages of the disease. However, limited data are available on the levels of CX3CL1 in the cerebrospinal fluid (CSF) and blood. Additionally, to date, its utility as a biomarker for MCI or AD has not been studied. The aim of the present study was to evaluate the clinical utility of CX3CL1 in the early diagnosis of cognitive impairment. We also compared the diagnostic usefulness of CX3CL1 with other biomarkers associated with neuroinflammation. A total of 60 patients with cognitive impairment, including 42 patients with AD and 18 subjects with MCI, as well as 20 cognitively healthy controls were enrolled in the study. CSF and blood concentrations of CX3CL1, CCL-2, and YKL-40 were measured by ELISA. Significantly higher CSF and blood concentrations of CX3CL1 were observed in MCI and AD patients compared to older individuals without cognitive impairment. The increase in the levels of CX3CL1 and YKL-40 in non-demented subjects was associated with MCI. The area under the ROC curve for CX3CL1 in MCI subjects was larger in comparison to classical AD markers. Presented results indicate a crucial role of CX3CL1 in the pathology of cognitive impairment and the potential usefulness of this protein in the early diagnosis of MCI and AD.

Memória, imagens, palavras: uma leitura de Magrite à luz da Literatura

O artigo propõe a leitura da tela A memória (1948), de René Magritte, como uma espécie de compilação das teorias mais importantes da memória. Para tanto, a discussão perpassará cada elemento que compõe a tela – uma fronte em mármore, um guizo, uma folha, uma cortina vermelha e um céu repleto de nuvens – buscando compreender a problematização do conceito de memória proposto pelo autor em imagens. Nesse sentido, temas adjacentes serão colocados em pauta, dentre eles as metáforas da memória mais recorrentes, como a do livro, sobretudo em Dante Aliguieri; a relação entre memória e morte, especialmente no que diz respeito ao trauma, que discutiremos a partir do tratado de retórica clássica Ad Herenium, bem como a própria relação entre passado, presente e futuro, lido aqui de Aristóteles a Lewis Carrol. Nesse sentido, partindo de uma análise comparativa entre a tela e alguns textos literários e teóricos, o artigo se propõe a compreender do que trata a memória para René Magritte.Palavras-chave: memória; mnemotécnica; escrita; tempo; esquecimento

Medical and surgical management of acute type B aortic intramural hematoma.

Type B acute aortic dissection (AAD) and intramural hematoma (IMH) can both present as potentially catastrophic lesions of the descending aorta. IMH is distinguished from AAD by the absence of an intimal tear and flap. With short-term outcomes being similar to type B AAD, IMH is treated identically to AAD in the corresponding segment of the aorta. While all patients with any acute aortic syndrome of the descending aorta receive prompt anti-impulse therapy, thoracic endovascular aortic repair (TEVAR) is reserved for patients presenting with certain complications, namely malperfusion, rupture, or periaortic hematoma. Technical aspects of TEVAR for IMH include maximal endograft oversizing of 10% with 20 mm landing zones of the healthy aorta, revascularization of the left subclavian artery when covered, use of cerebrospinal fluid drainage with extensive coverage, and restoration of branch vessel perfusion. With respect to disease evolution, IMH may progress to classic AD, frank rupture, or aneurysmal dilation; yet, IMH may also regress and be completely resorbed. However, since the natural history of IMH is unpredictable, TEVAR is being used more aggressively to improve long-term survival, rates of secondary reintervention, and positive aortic remodeling. Much remains unknown for acute type B IMH, including the use of prophylactic TEVAR for stable uncomplicated presentations, as well as the optimal timing of intervention and certain technical aspects of TEVAR. As such, IMH remains a diagnostic and therapeutic challenge for cardiovascular surgeons.

Classical dS and AdS cosmologies in the general case of deformed space with minimal length

Classical dS and AdS cosmologies in the general case of deformed space with minimal length

Classical dS and AdS cosmologies in the general case of deformed space with minimal length

Classical dS and AdS cosmologies in the general case of deformed space with minimal length

18F]-AV-1451 binding profile in chronic traumatic encephalopathy: a postmortem case series

IntroductionChronic traumatic encephalopathy (CTE) is a tauopathy associated to repetitive head trauma. There are no validated in vivo biomarkers of CTE and a definite diagnosis can only be made at autopsy. Recent studies have shown that positron emission tomography (PET) tracer AV-1451 (Flortaucipir) exhibits high binding affinity for paired helical filament (PHF)-tau aggregates in Alzheimer (AD) brains but relatively low affinity for tau lesions in other tauopathies like temporal lobal degeneration (FTLD)-tau, progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). Little is known, however, about the binding profile of this ligand to the tau-containing lesions of CTE.ObjectiveTo study the binding properties of [18F]-AV-1451 on pathologically confirmed CTE postmortem brain tissue samples.MethodsWe performed [18F]-AV-1451 phosphor screen and high resolution autoradiography, quantitative tau measurements by immunohistochemistry and Western blot and tau seeding activity assays in brain blocks containing hippocampus, superior temporal cortex, superior frontal cortex, inferior parietal cortex and occipital cortex from 5 cases of CTE, across the stages of disease: stage II-III (n = 1), stage III (n = 3), and stage IV (n = 1). Importantly, low or no concomitant classic AD pathology was present in these brains.ResultsDespite the presence of abundant tau aggregates in multiple regions in all CTE brains, only faint or no [18F]-AV-1451 binding signal could be detected by autoradiography. The only exception was the presence of a strong signal confined to the region of the choroid plexus and the meninges in two of the five cases. Tau immunostaining and Thioflavin-S staining ruled out the presence of tau aggregates in those regions. High resolution nuclear emulsion autoradiography revealed the presence of leptomeningeal melanocytes as the histologic source of this off-target binding. Levels of abnormally hyperphosphorylated tau species, as detected by Western Blotting, and tau seeding activity were both found to be lower in extracts from cases CTE when compared to AD.ConclusionAV-1451 may have limited utility for in vivo selective and reliable detection of tau aggregates in CTE. The existence of disease-specific tau conformations may likely explain the differential binding affinity of this tracer for tau lesions in different tauopathies.

Parkinson's and Lewy body dementia CSF biomarkers

The clinical diagnosis of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) is challenging due to highly variable clinical presentation and clinical and pathological overlap with other neurodegenerative diseases. Since cerebrospinal fluid (CSF) mirrors the pathological changes taking place in the brain, it represents a promising source of biomarkers.With respect to classical AD biomarkers, low CSF Aβ42 levels have shown a robust prognostic value in terms of development of cognitive impairment in PD and DLB. In the differential diagnosis between AD and DLB, a potential role of t-tau, p-tau and Aβ42/Aβ38 ratio has been demonstrated. Regarding CSF α-synuclein (α-syn) species, lower levels of total α-synuclein (t-α-syn) and higher concentration of oligomeric-α-synuclein (o-α-syn) and phosphorylated α-synuclein (p-α-syn) have been observed in PD. Furthermore, the detection of “pro-aggregating” α-synuclein has enabled the discrimination of patients affected by synucleinopathies with high sensitivity and specificity. New promising biomarkers are emerging: GCase activity (reduced in PD and DLB patients vs. controls), CSF/serum albumin ratio (increased in PD and DLB), fatty-acid-binding protein (increased in AD and DLB vs. PD), visinin-like protein-1 (increased in AD vs. DLB) and monoamines (useful in differential diagnosis among PD and DLB). These encouraging results need to be confirmed by future studies.

PRINCIPLES OF MODELING OF THE GENERAL ECONOMIC EQUILIBRIUM

This paper focuses on formulation of the principles of macroeconomic modeling and their implementation in the theory of general dynamic equilibrium. The subject of the theoretical study is a closed private economy, in which two macroeconomic actors – households and investment firms – interact. Known general scientific principles – the analysis of dimensions, homogeneity and correspondence – are supplemented by specific principles that allow us to obtain an analytical form of behavioral functions. The general properties of these functions are analyzed from the point of view of utility theory. The relationship between the equations of profit and profitability dynamics and the forms of investment function is revealed. A comparative analysis of their properties is carried out. The functions of rates of payment for resources, which take into account their limitations, are proposed. It is shown that endogenous cyclic fluctuations arise in the classical AD – AS model, supplemented by equations of the dynamics of fixed capital and profitability. A mathematical analysis of the proposed model is carried out and its graphical interpretation is given using long-run curves of aggregate demand and aggregate supply. Indicators of the state of long-run equilibrium and the condition of its stability are determined.The possible directions of the proposed model are considered. In particular, it is shown that this model can include a financial market in which households and investment firms directly lend money to each other. This market can be represented using two symmetric demand-supply functions that link the interest rate, present and expected future cash reserves.

What We Learn from the CTAD (Clinical Trials Alzheimer's Disease) 2018.

Several ongoing clinical development programs are investigating potential disease-modifying treatments for Alzheimer's disease (AD), including lanabecestat (AZD3293/LY3314814). Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Aβ) precursor protein-cleaving enzyme 1 (BACE1) that reduces Aβ production. As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aβ species and soluble amyloid precursor proteins (sAPPβ) in mouse, guinea pig, and dog in a time- and dose-dependent manner. Significant reductions in plasma and cerebrospinal fluid (CSF) Aβ1-40 and Aβ1-42 were observed in Phase 1 studies of healthy subjects and AD patients treated with lanabecestat. Three lanabecestat trials are ongoing and intended to support registration in Early AD: (1) Phase 2/3 study in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia (AMARANTH, NCT02245737); (2) Delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study; and (3) Phase 3 study in mild AD dementia (DAYBREAK-ALZ, NCT02783573). This review will discuss the development of lanabecestat, results from the completed nonclinical and clinical studies, as well as describe the ongoing Phase 3 clinical trials.

Temporal association patterns and dynamics of amyloid-\u03b2 and tau in Alzheimer\u2019s disease

The elusive relationship between underlying pathology and clinical disease hampers diagnosis of Alzheimer’s disease (AD) and preventative intervention development. We seek to understand the relationship between two classical AD biomarkers, amyloid-β1−42 (Aβ1−42) and total-tau (t-tau), and define their trajectories across disease development, as defined by disease onset at diagnosis of mild cognitive impairment (MCI). Using longitudinal data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we performed a correlation analysis of biomarkers CSF Aβ1−42 and t-tau, and longitudinal quantile analysis. Using a mixed effects model, with MCI onset as an anchor, we develop linear trajectories to describe the rate of change across disease development. These trajectories were extended through the incorporation of data from cognitively normal, healthy adults (aged 20–62 years) from the literature, to fit sigmoid curves by means of non-linear least squares estimators, to create curves encompassing the 50 years prior to MCI onset. A strong right-angled relationship between the biomarkers Aβ1-42 and t-tau is detected, implying a highly non-linear relationship. The rate of change of Aβ1-42 is correlated with the baseline concentration per quantile, reflecting a reduction in the rate of loss across disease within subjects. Regression models reveal significant amyloid loss relative to MCI onset (− 2.35 pg/mL/year), compared to minimal loss relative to AD onset (− 0.97 pg/mL/year). Tau accumulates consistently relative to MCI and AD onset, (2.05 pg/mL/year) and (2.46 pg/mL/year), respectively. The fitted amyloid curve shows peak loss of amyloid 8.06 years prior to MCI diagnosis, while t-tau exhibits peak accumulation 14.17 years following MCI diagnosis, with the upper limit not yet reached 30 years post diagnosis. Biomarker trajectories aid unbiased, objective assessment of disease progression. Quantitative trajectories are likely to be of use in clinical trial design, as they allow for a more detailed insight into the effectiveness of treatments designed to delay development of biological disease.