Related amyloid burden and cortical atrophy in individuals with subtle cognitive decline.

BACKGROUND AND PURPOSE: Subtle cognitive decline represents a stage of cognitive deterioration in which pathological biomarkers may be present, including early cortical atrophy and amyloid deposition. Using individual items from the Montreal Cognitive Assessment and k-modes cluster analysis, we previously identified three clusters of individuals without overt cognitive impairment: (1) High Performing (no deficits in performance), (2) Memory Deficits (lower memory performance), and (3) Compound Deficits (lower memory and executive function performance). In this study, we sought to understand the relationships found in our clusters between cortical atrophy on MR and amyloid burden on PET. METHODS: Data were derived from the Alzheimer's Disease Neuroimaging Initiative and comprised individuals from our previous analyses with available MR and amyloid PET scans (n = 272). Using multiple-group structural equation modeling, we regressed amyloid standardized uptake value ratio on volumetric regions to simultaneously evaluate unique associations within each cluster. RESULTS: In our Compound Deficits cluster, greater whole cerebral amyloid burden was significantly related to right entorhinal cortical and left hippocampal atrophy, rs  = -.412 (p = .005) and -.304 (p = .049), respectively. Within this cluster, right entorhinal cortical atrophy was significantly related to greater amyloid burden within multiple frontal regions. CONCLUSIONS: The Compound Deficits cluster, which represents a group potentially at higher risk for decline, was observed to have significantly more cortical atrophy, particularly within the entorhinal cortex and hippocampus, associated with whole brain and frontal lobe amyloid burden. These findings point to a pattern of early pathological deterioration that may place these individuals at risk for future decline.

A case of Tn polyagglutination discovered by an ABO blood group discrepancy.

BACKGROUND: Tn syndrome is an acquired form of polyagglutination arising from somatic mutations of hematopoietic stem cells. Tn red blood cells (RBCs) are agglutinable by naturally occurring anti-Tn antibodies in most adult sera. Current ABO typing reagents are monoclonal and do not detect polyagglutination on forward typing. However, herein we describe a case of Tn activation that was suspected due to cross-reactivity with a monoclonal anti-A reagent. STUDY DESIGN AND METHODS: A 63-year-old man with myeloproliferative neoplasm, who historically typed as group O, demonstrated unexpected mixed field reactivity with anti-A reagent using a gel-based method. However, manual tube testing was consistent with the patient's historical group O type. RESULTS: Lectin testing demonstrated reactivity with Salvia sclarea and Glycine soja, but not Arachis hypogea. The patient's RBCs produced positive crossmatches with healthy donor sera, but reactivity was eliminated by ficin pretreatment of the RBCs. Ficin treatment also resolved typing discrepancies on gel-based typing. No reactivity was noted using cord blood sera, and N antigen expression was diminished upon phenotyping. Tn activation was confirmed by detection of a novel 4-nucleotide deletion (c.395-398del) in exon 3 of C1GALT1C1 resulting in a truncated glycosyltransferase. CONCLUSION: This case of acquired Tn polyagglutination due to a novel mutation was first suspected from an ABO phenotyping discrepancy. It highlights the cross-reactivity of anti-A reagent with Tn antigen when tested on a common gel-based method. Furthermore, the case demonstrates that review of patient history and test information can clarify discrepancies and guide resolution.

Characteristics of subjective cognitive decline associated with amyloid positivity.

INTRODUCTION: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. METHODS: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms with amyloid positivity. RESULTS: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE ε4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. DISCUSSION: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.

Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aß-related cognitive impairment in preclinical Alzheimer's disease after a 27-month delay interval.

BACKGROUND: Abnormal beta-amyloid (Aß) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1-4, 2017). Previously, we established the scopolamine challenge test (SCT) as a "cognitive stress test" screening measure to identify individuals at risk for AD (Alzheimer's & Dementia 10(2):262-7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval. METHODS: Older adults (N = 63, aged 55-75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam. RESULTS: Significant differences in both cognitive performance and in Aß neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period. CONCLUSIONS: Cognitive response to the SCT (Alzheimer's & Dementia 10(2):262-7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.

Developing retinal biomarkers for the earliest stages of Alzheimer's disease: What we know, what we don't, and how to move forward.

The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and toward validation of AD risk biomarkers that could potentially be used as a first step in a multistep screening process for AD risk detection.

G-protein-coupled estrogen receptor 1 is anatomically positioned to modulate synaptic plasticity in the mouse hippocampus.

Both estrous cycle and sex affect the numbers and types of neuronal and glial profiles containing the classical estrogen receptors α and ß, and synaptic levels in the rodent dorsal hippocampus. Here, we examined whether the membrane estrogen receptor, G-protein-coupled estrogen receptor 1 (GPER1), is anatomically positioned in the dorsal hippocampus of mice to regulate synaptic plasticity. By light microscopy, GPER1-immunoreactivity (IR) was most noticeable in the pyramidal cell layer and interspersed interneurons, especially those in the hilus of the dentate gyrus. Diffuse GPER1-IR was found in all lamina but was most dense in stratum lucidum of CA3. Ultrastructural analysis revealed discrete extranuclear GPER1-IR affiliated with the plasma membrane and endoplasmic reticulum of neuronal perikarya and dendritic shafts, synaptic specializations in dendritic spines, and clusters of vesicles in axon terminals. Moreover, GPER1-IR was found in unmyelinated axons and glial profiles. Overall, the types and amounts of GPER1-labeled profiles were similar between males and females; however, in females elevated estrogen levels generally increased axonal labeling. Some estradiol-induced changes observed in previous studies were replicated by the GPER agonist G1: G1 increased PSD95-IR in strata oriens, lucidum, and radiatum of CA3 in ovariectomized mice 6 h after administration. In contrast, estradiol but not G1 increased Akt phosphorylation levels. Instead, GPER1 actions in the synapse may be due to interactions with synaptic scaffolding proteins, such as SAP97. These results suggest that although estrogen's actions via GPER1 may converge on the same synaptic elements, different pathways are used to achieve these actions.

Post-synaptic density-95 (PSD-95) binding capacity of G-protein-coupled receptor 30 (GPR30), an estrogen receptor that can be identified in hippocampal dendritic spines.

The estrogen 17ß-estradiol (E2) modulates dendritic spine plasticity in the cornu ammonis 1 (CA1) region of the hippocampus, and GPR30 (G-protein coupled estrogen receptor 1 (GPER1)) is an estrogen-sensitive G-protein-coupled receptor (GPCR) that is expressed in the mammalian brain and in specific subregions that are responsive to E2, including the hippocampus. The subcellular localization of hippocampal GPR30, however, remains unclear. Here, we demonstrate that GPR30 immunoreactivity is detected in dendritic spines of rat CA1 hippocampal neurons in vivo and that GPR30 protein can be found in rat brain synaptosomes. GPR30 immunoreactivity is identified at the post-synaptic density (PSD) and in the adjacent peri-synaptic zone, and GPR30 can associate with the spine scaffolding protein PSD-95 both in vitro and in vivo. This PSD-95 binding capacity of GPR30 is specific and determined by the receptor C-terminal tail that is both necessary and sufficient for PSD-95 interaction. The interaction with PSD-95 functions to increase GPR30 protein levels residing at the plasma membrane surface. GPR30 associates with the N-terminal tandem pair of PDZ domains in PSD-95, suggesting that PSD-95 may be involved in clustering GPR30 with other receptors in the hippocampus. We demonstrate that GPR30 has the potential to associate with additional post-synaptic GPCRs, including the membrane progestin receptor, the corticotropin releasing hormone receptor, and the 5HT1a serotonin receptor. These data demonstrate that GPR30 is well positioned in the dendritic spine compartment to integrate E2 sensitivity directly onto multiple inputs on synaptic activity and might begin to provide a molecular explanation as to how E2 modulates dendritic spine plasticity.

Age- and hormone-regulation of opioid peptides and synaptic proteins in the rat dorsal hippocampal formation.

Circulating estrogen levels and hippocampal-dependent cognitive functions decline with aging. Moreover, the responses of hippocampal synaptic structure to estrogens differ between aged and young rats. We recently reported that estrogens increase levels of post-synaptic proteins, including PSD-95, and opioid peptides leu-enkephalin and dynorphin in the hippocampus of young animals. However, the influence of ovarian hormones on synaptic protein and opioid peptide levels in the aging hippocampus is understudied. Here, young (3- to 5-month-old), middle-aged (9- to 12-month-old), and aged (about 22-month-old) female rats were ovariectomized and then, 4 weeks later, subcutaneously implanted with a silastic capsule containing vehicle or 17ß-estradiol. After 48 h, rats were subcutaneously injected with progesterone or vehicle and sacrificed 1 day later. Coronal sections through the dorsal hippocampus were processed for quantitative peroxidase immunohistochemistry of leu-enkephalin, dynorphin, synaptophysin, and PSD-95. With age, females showed opposing changes in leu-enkephalin and dynorphin levels in the mossy fiber pathway, particularly within the hilus, and regionally specific changes in synaptic protein levels. 17ß-estradiol, with or without progesterone, altered leu-enkephalin levels in the dentate gyrus and synaptophysin levels in the CA1 of young but not middle-aged or aged females. Additionally, 17ß-estradiol decreased synaptophysin levels in the CA3 of middle-aged females. Our results support and extend previous findings indicating 17ß-estradiol modulation of hippocampal opioid peptides and synaptic proteins while demonstrating regional and age-specific effects. Moreover, they lend credence to the "window of opportunity" hypothesis during which hormone replacement can modulate hippocampal structure and circuitry to improve cognitive outcomes.

Distribution of estrogen receptor ß containing cells in the brains of bacterial artificial chromosome transgenic mice.

In the brain, estrogen receptor beta (ERbeta) plays important roles in autonomic functions, stress reactivity and learning and memory processes. However, understanding the function of ERbeta has been restricted by the limited availability of specific antisera, by difficulties discriminating the discrete localization of ERbeta-immunoreactivity (ir) at the light microscopic level in many brain regions and the identification of ERbeta-containing neurons in neurophysiological and molecular studies. Here, we demonstrate that a Esr2 bacterial artificial chromosome (BAC) transgenic mouse line that expresses ERbeta identified by enhanced green fluorescent protein (EGFP) overcomes these shortcomings. Throughout the brain, ERbeta-EGFP was detected in the nuclei and cytoplasm of cells, the majority of which resembled neurons. EGFP often extended into dendritic processes and could be identified either natively or following intensification of EGFP using immunolabeling. The distribution of ERbeta-EGFP cells in brain closely corresponded to that reported for ERbeta protein and mRNA. In particular, ERbeta-EGFP cells were found in autonomic brain regions (i.e., hypothalamic paraventricular nucleus, rostral ventrolateral medulla and nucleus of the solitary tract), in regions associated with anxiety and stress behaviors (i.e., bed nucleus of the stria terminalis, amygdala, periaqueductal gray, raphe and parabrachial nuclei) and in regions involved in learning and memory processes (i.e., basal forebrain, cerebral cortex and hippocampus). Additionally, dual label light and electron microscopic studies in select brain areas demonstrate that cell containing ERbeta-EGFP colocalize with both nuclear and extranuclear ERbeta-immunoreactivity. These findings support the utility of Esr2 BAC transgenic reporter mice for future studies understanding the role of ERbeta in CNS function.