Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals

BACKGROUND AND OBJECTIVES: To test the associations between the presynaptic growth-associated protein 43 (GAP-43) protein, quantified in cerebrospinal fluid (CSF), and biomarkers of Alzheimer's disease (AD) pathophysiology, cross-sectionally and longitudinally. METHODS: In this retrospective study, GAP-43 was measured in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort using an in-house ELISA method, and levels were compared between groups, both cross-sectionally and longitudinally. Linear regression models tested the associations between biomarkers of AD (Aβ and tau pathologies, neurodegeneration and cognition) adjusted by age, sex and diagnosis. Linear mixed effect models (LME) evaluated how baseline GAP-43 predicts brain hypometabolism, atrophy and cognitive decline over time. Cox-proportional hazard regression models tested how GAP-43 levels and Aβ status, at baseline, increased the risk of progression to AD dementia over time. RESULTS: This study included 786 participants from the ADNI cohort, which were further classified in cognitively unimpaired (CU) Aβ-negative (nCU-=197); CU Aβ-positive (nCU+=55), mild cognitively impaired (MCI) Aβ-negative (nMCI-=228), MCI Aβ-positive (nMCI+=193) and AD dementia Aβ-positive (nAD=113). CSF GAP-43 levels were increased in Aβ-positive compared to Aβ-negative participants, independent of the cognitive status. In Aβ-positive participants, high baseline GAP-43 levels led to worse brain metabolic decline (P=0.01), worse brain atrophy (P=8.8x10-27) as well as worse MMSE scores (P= 0.03) over time, as compared to those with low GAP-43 levels. Similarly, Aβ-positive participants with high baseline GAP-43 had the highest risk to convert to AD dementia (hazard ratio [HR=8.56, 95% CI, 4.94-14.80, P=1.5x10-14]). Despite the significant association with Aβ pathology (η 2 Aβ PET=0.09, P Aβ PET<0.001), CSF tTau and P-Tau had a larger effect size on GAP43 than had Aβ PET (η 2 pTau-181=0.53, P pTau-181<0.001; η 2 tTau=0.59, P tTau<0.001). CONCLUSIONS: and Classification of Evidence: This study provides Class III classification of evidence that high baseline levels of CSF GAP-43 are associated to progression in Aβ-positive individuals, with a more aggressive neurodegenerative process, faster rate of cognitive decline and increased risk of converting to dementia

Comparison of the Effects of Three Insulinotropic Drugs on Plasma Insulin Levels After a Standard Meal

OBJECTIVE—To compare the effects of repaglinide, glipizide, and glibenclamide on insulin secretion and postprandial glucose after a single standard 500-kcal test meal. RESEARCH DESIGN AND METHODS—A total of 12 type 2 diabetic patients with early diabetes (mean HbA1c of 6.1%) and 12 matched control subjects were enrolled in this randomized, double-blind, crossover trial. Subjects received placebo, 2 mg repaglinide, 5 mg glipizide, and 5 mg glibenclamide in a random fashion during the trial. Administration of each drug was followed by a single standard 500-kcal test meal. A washout period of 7–12 days existed between the four study visits. RESULTS—All three drugs were equally effective on the total prandial insulin secretion (area under the curve [AUC] ?15 to 240 min). However, clear differences were noted in the early insulin secretion (AUC ?15 to 30 min); both repaglinide and glipizide increased secretion in nondiabetic subjects by ?61 and 34%, respectively, compared with placebo. In the diabetic patients, the difference versus placebo was 37 and 47%, respectively. The difference between glipizide and glibenclamide reached significance in both groups of subjects, whereas repaglinide was more effective than glibenclamide only in the healthy nondiabetic subject group. All three drugs were effective in decreasing total glucose AUC in the nondiabetic and diabetic population. In the nondiabetic subjects, however, repaglinide was significantly more effective than glibenclamide. The differences disappeared in the diabetic subjects, probably as a result of increased prevalence of insulin resistance in this group. CONCLUSIONS—Repaglinide and glipizide but not glibenclamide significantly enhanced the early insulin secretion in both nondiabetic and diabetic subjects with preserved ?-cell function after a single standard meal

Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the alzheimer's disease neuroimaging initiative

Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-β (Aβ) and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aβ and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aβ PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aβ PET scans show little increase but plasma p-tau181 is increased if CSF Aβ has already changed prior to Aβ PET changes. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC = 85.3%; 95% CI, 81.4-89.2%), as well as to distinguish between Aβ- and Aβ+ individuals along the Alzheimer's continuum (AUC = 76.9%; 95% CI, 74.0-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.Data collection and sharing was funded by ADNI (NIH #U01 AG024904) and DOD ADNI (#W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisa i Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Ph armaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. TKK holds a Brightfocus fellowship (#A2020812F), and is further supported by the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-930627), the Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), the Swedish Dementia Foundation (Demensförbundet), the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Anna Lisa and Brother Björnsson’s Foundation, Gamla Tjänarinnor, and the Gun and Bertil Stohnes Foundation. NJA is supported by the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-931009), the Swedish Brain Foundation (Hjärnfonden), the Agneta Prytz-Folkes & Gösta Folkes Foundation, and the Swedish Dementia Foundation (Demensförbundet). AS was supported by the Emil Aaltonen Foundation and the Paul o Foundation, and currently receives funding from the Orion Research Foundation. MS-C received funding fro m the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skl odowska-Curie action grant agreement No 752310, and currently receives funding from Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I). PR-N is supported by the Weston Brain Institute, the Canadian Institutes of Health Research, the Canadian Consortium on Neurodegeneration in Aging and the Fonds de Recherche du Québec – Santé (FRQS; Chercheur Boursier, and 2020-VICO-279314 TRIAD/BIOVIE Cohort), the CIHR-CCNA Canadian Consortium of Neurodegeneration in Aging, and the Canada Foundation for Innovation (project 34874). KB was supported by the Alzheimer Drug Discovery Foundation (ADDF; #RDAPB- 201809-2016615), the Swedish Research Council (#2017-00915), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), and a grant (#ALFGBG-715986) from the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017- 0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF- agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019- 466-236). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (# ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL

An estrogen-dependent four-gene micronet regulating social recognition: A study with oxytocin and estrogen receptor-α and -β knockout mice

Estrogens control many physiological and behavioral processes, some of which are connected to reproduction. These include sexual and other social behaviors. Here we implicate four gene products in a micronet required for mammalian social recognition, through which an individual learns to recognize other individuals. Female mice whose genes for the neuropeptide oxytocin (OT) or the estrogen receptor (ER)-β or ER-α had been selectively “knocked out” were deficient specifically in social recognition and social anxiety. There was a remarkable parallelism among results from three separate gene knockouts. The data strongly suggest the involvement in social recognition of the four genes coding for ER-α, ER-β, OT, and the OT receptor. We thus propose here a four-gene micronet, which links hypothalamic and limbic forebrain neurons in the estrogen control over the OT regulation of social recognition. In our model, estrogens act on the OT system at two levels: through ER-β, they regulate the production of OT in the hypothalamic paraventricular nucleus, and through ER-α, they drive the transcription of the OT receptor in the amygdala. The proper operation of a social recognition mechanism allows for the expression of appropriate social behaviors, aggressive or affiliative

Evaluating the Impacts of Traditional Biomass Energy Use on Agricultural Production in Sichuan, China

As crop straw and firewood are generated as by-products of food production systems, they are perceived to be sustainable energy sources that do not threaten food security by Chinese government for a long time. However, the time spent on collecting straw and firewood may create a burden on rural household, as it could reduce the available labor inputs for agricultural production, which in turn, possibly brings negative impact on food security. Building on an integrated agriculture-energy production system, a Symmetric Normalized Quadratic (SNQ) multi-output profit function (which includes labor allocations as quasi-fixed factors) is estimated to investigate the impacts of traditional biomass energy use on agricultural production in this paper. The negative signs of the calculated cross-price elasticities of supply (agricultural products and biomass energy) confirm that the relationship between biomass collection and agricultural production is competition. Moreover, the cross-price elasticities of biomass collection with respect to inputs are positive, implying that indirect link between biomass collection and agricultural production perhaps lies in household consumption decisions. The important implication of this study is that potential policy interventions for developing biomass energy in rural China could aim at enhancing food security by improving household motivation of engaging in agricultural production and slowing down the competition between biomass collection and agricultural production. It is suggested that government should attach more importance to simultaneously promote the prices of agricultural products and control the prices of intermediate inputs