Concepcion Conejero-Goldberg

Utility of Combinations of Biomarkers, Cognitive Markers, and Risk Factors to Predict Conversion From Mild Cognitive Impairment to Alzheimer Disease in Patients in the Alzheimer's Disease Neuroimaging Initiative

CONTEXTnBiomarkers have become increasingly important in understanding neurodegenerative processes associated with Alzheimer disease. Markers include regional brain volumes, cerebrospinal fluid measures of pathological Aβ1-42 and total tau, cognitive measures, and individual risk factors.nnnOBJECTIVEnTo determine the discriminative utility of different classes of biomarkers and cognitive markers by examining their ability to predict a change in diagnostic status from mild cognitive impairment to Alzheimer disease.nnnDESIGNnLongitudinal study.nnnPARTICIPANTSnWe analyzed the Alzheimers Disease Neuroimaging Initiative database to study patients with mild cognitive impairment who converted to Alzheimer disease (nxa0=xa0116) and those who did not convert (nxa0=xa0204) within a 2-year period. We determined the predictive utility of 25 variables from all classes of markers, biomarkers, and risk factors in a series of logistic regression models and effect size analyses.nnnSETTINGnThe Alzheimers Disease Neuroimaging Initiative public database.nnnOUTCOME MEASURESnPrimary outcome measures were odds ratios, pseudo- R(2)s, and effect sizes.nnnRESULTSnIn comprehensive stepwise logistic regression models that thus included variables from all classes of markers, the following baseline variables predicted conversion within a 2-year period: 2 measures of delayed verbal memory and middle temporal lobe cortical thickness. In an effect size analysis that examined rates of decline, change scores for biomarkers were modest for 2 years, but a change in an everyday functional activities measure (Functional Assessment Questionnaire) was considerably larger. Decline in scores on the Functional Assessment Questionnaire and Trail Making Test, part B, accounted for approximately 50% of the predictive variance in conversion from mild cognitive impairment to Alzheimer disease.nnnCONCLUSIONSnCognitive markers at baseline were more robust predictors of conversion than most biomarkers. Longitudinal analyses suggested that conversion appeared to be driven less by changes in the neurobiologic trajectory of the disease than by a sharp decline in functional ability and, to a lesser extent, by declines in executive function.

Performance-Based Measures of Everyday Function in Mild Cognitive Impairment

OBJECTIVEnThe view that everyday function is preserved in mild cognitive impairment may be problematic. The objectives of this study were to determine the magnitude of impairment in everyday function in patients with mild cognitive impairment and Alzheimers disease using a novel sensitive performance-based measure (the UCSD Performance-Based Skills Assessment; UPSA), contrast it with use of an informant-based measure (the Alzheimers Disease Cooperative Study-Activities of Daily Living Inventory; ADCS-ADL), and model the relationship between cognitive measures and the performance-based measure.nnnMETHODnFifty cognitively normal elders, 26 patients who met criteria for amnestic mild cognitive impairment, and 22 patients who suffered from mild to moderate Alzheimers disease were assessed on the UPSA, the ADCS-ADL, and a battery of neurocognitive tests.nnnRESULTSnPatients with mild cognitive impairment had significant impairments on the UPSA but not on the ADCS-ADL. The magnitude of the effect size between the cognitively healthy and the mild cognitive impairment group for the UPSA was large (d=0.86). A strong and significant relationship was observed between cognitive performances in speed (R(2)=0.37), episodic memory (R(2)=0.10), and semantic processing (R(2)=0.03) and UPSA score using multiple regression models. The psychometric properties of the UPSA were acceptable, as were its sensitivity and specificity in contrasts between cognitively normal elders and patients with mild cognitive impairment and between the latter group and patients with Alzheimers disease.nnnCONCLUSIONSnThese findings indicate that performance-based measures of function may be a sensitive tool in studies of Alzheimers disease and mild cognitive impairment and suggest the need for a reconceptualization of the relationship between cognition and function in mild cognitive impairment so that they can be usefully aligned.

Alpha7 nicotinic acetylcholine receptor: A link between inflammation and neurodegeneration

Alzheimers disease (AD) is the leading cause of dementia affecting over 25 million people worldwide. Classical studies focused on the description and characterization of the pathological hallmarks found in AD patients including the neurofibrillary tangles and the amyloid plaques. Current strategies focus on the etiology of these hallmarks and the different mechanisms contributing to neurodegeneration. Among them, recent studies reveal the close interplay between the immunological and the neurodegenerative processes. This article examines the implications of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) as a critical link between inflammation and neurodegeneration in AD. Alpha7nAChRs are not only expressed in neurons but also in Glia cells where they can modulate the immunological responses contributing to AD. Successful therapeutic strategies against AD should consider the connections between inflammation and neurodegeneration. Among them, alpha7nAChR may represent a pharmacological target to control these two mechanisms during the pathogenesis of neurodegenerative and behavioral disorders.

Extension and refinement of the predictive value of different classes of markers in ADNI: Four year follow-up data

This study examined the predictive value of different classes of markers in the progression from mild cognitive impairment (MCI) to Alzheimers disease (AD) over an extended 4‐year follow‐up in the Alzheimers Disease Neuroimaging Initiative (ADNI) database.

Alpha7 cholinergic-agonist prevents systemic inflammation and improves survival during resuscitation

Severe haemorrhage is a common cause of death despite the recent advances in critical care. Conventional resuscitation fluids are designed to re‐establish tissue perfusion, but they fail to prevent inflammatory responses during resuscitation. Our previous studies indicated that the vagus nerve can modulate systemic inflammation via the alpha7 nicotinic acetylcholine receptor (α7nAchR). Here, we report that the alpha7nAChR‐agonist, GTS, restrains systemic inflammation and improves survival during resuscitation. Resuscitation with GTS rescued all the animals from lethal haemorrhage in a concentration‐dependent manner. Unlike conventional resuscitation fluids, GTS inhibited the production of characteristic inflammatory and cardiodepressant factors including tumour necrosis factor (TNF) and high mobility group B protein‐1 (HMGB1). Resuscitation with GTS was particularly effective in restraining systemic TNF responses and inhibiting its production in the spleen. At the molecular level, GTS inhibited p65RelA but not RelB NF‐κB during resuscitation. Unlike non‐specific nicotinic agonists, GTS inhibited serum protein TNF levels in both normal and splenectomized, haemorrhagic animals. Resuscitation with GTS inhibited poly(ADP‐ribose) polymerase and systemic HMGB1 levels. Our studies suggest that GTS provides significant advantages as compared with non‐specific nicotinic agonists, and it could be a promising anti‐inflammatory supplement to improve survival during resuscitation.

Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer's disease as based on APOE genotype

Alzheimers disease (AD) is a neurodegenerative condition characterized histopathologically by neuritic plaques and neurofibrillary tangles. The objective of this transcriptional profiling study was to identify both neurosusceptibility and intrinsic neuroprotective factors at the molecular level, not confounded by the downstream consequences of pathology. We thus studied post-mortem cortical tissue in 28 cases that were non-APOE4 carriers (called the APOE3 group) and 13 cases that were APOE4 carriers. As APOE genotype is the major genetic risk factor for late-onset AD, the former group was at low risk for development of the disease and the latter group was at high risk for the disease. Mean age at death was 42 years and none of the brains had histopathology diagnostic of AD at the time of death. We first derived interregional difference scores in expression between cortical tissue from a region relatively invulnerable to AD (primary somatosensory cortex, BA 1/2/3) and an area known to be susceptible to AD pathology (middle temporal gyrus, BA 21). We then contrasted the magnitude of these interregional differences in between-group comparisons of the APOE3 (low risk) and APOE4 (high risk) genotype groups. We identified 70 transcripts that differed significantly between the groups. These included EGFR, CNTFR, CASP6, GRIA2, CTNNB1, FKBPL, LGALS1 and PSMC5. Using real-time quantitative PCR, we validated these findings. In addition, we found regional differences in the expression of APOE itself. We also identified multiple Kyoto pathways that were disrupted in the APOE4 group, including those involved in mitochondrial function, calcium regulation and cell-cycle reentry. To determine the functional significance of our transcriptional findings, we used bioinformatics pathway analyses to demonstrate that the molecules listed above comprised a network of connections with each other, APOE, and APP and MAPT. Overall, our results indicated that the abnormalities that we observed in single transcripts and in signaling pathways were not the consequences of diagnostic plaque and tangle pathology, but preceded it and thus may be a causative link in the long molecular prodrome that results in clinical AD.

MAPT isoforms: differential transcriptional profiles related to 3R and 4R splice variants.

Tau aggregation in neurofibrillary tangles is a pathological hallmark in tauopathies including Alzheimers disease (AD). The predominant aggregation of certain MAPT (tau gene) isoforms, either the 4-repeat (4R tau) or the 3-repeat (3R tau) isoform has been widely described in tauopathies. Alterations of the 4R tau to 3R tau ratio may be a key for tau-related neurodegeneration. To study the biological consequences in expression between tau splicing isoforms 4R and 3R, we analyzed the main neurobiological effects of inclusion of the repeat region coded by exon 10 in MAPT. We compared the transcriptional profiles of the 4R tau isoforms to 3R tau isoforms using whole-genome gene expression profiling microarrays using human neuroblastoma SH-SY5Y cell lines overexpressing either human 4R tau or 3R tau isoforms. We identified 68 transcripts that differed significantly (at p < 0.001) between 4R and 3R isoforms as conditioned on a second variant, the so-called 2N inclusion. We extended these findings in a 2 × 2 ANOVA to examine interaction effects of these variants. Transcripts involved in embryonic development were downregulated when exon 10 was present, while transcripts related to outgrowth of neurites were generally upregulated. An important pathway implicated in AD also differed between the 3R and 4R cell lines, Wnt signaling. These studies demonstrate expression differences between MAPT isoforms 4R tau and 3R tau due to the inclusion/exclusion of the repeat region coded for by exon 10. Our data add to complex findings on the role of 3R/4R in normal and abnormal neuronal function and highlight several molecular mechanisms that might drive neurodegeneration, or perhaps, set the stage for it.

APOE Genotype Modulates Proton Magnetic Resonance Spectroscopy Metabolites in the Aging Brain

BACKGROUNDnProton magnetic resonance spectroscopy ((1)H-MRS) studies on healthy aging have reported inconsistent findings and have not systematically taken into account the possible modulatory effect of APOE genotype. We aimed to quantify brain metabolite changes in healthy subjects in relation to age and the presence of the APOE E4 genetic risk factor for Alzheimers disease. Additionally, we examined these measures in relation to cognition.nnnMETHODSnWe studied a cohort of 112 normal adults between 50 and 86 years old who were genotyped for APOE genetic polymorphism. Measurements of (1)H-MRS metabolites were obtained in the posterior cingulate and precuneus region. Measures of general cognitive functioning, memory, executive function, semantic fluency, and speed of processing were also obtained.nnnRESULTSnGeneral linear model analysis demonstrated that older APOE E4 carriers had significantly higher choline/creatine and myo-inositol/creatine ratios than APOE E3 homozygotes. Structural equation modeling resulted in a model with an excellent goodness of fit and in which the APOE × age interaction and APOE status each had a significant effect on (1)H-MRS metabolites (choline/creatine and myo-inositol/creatine). Furthermore, the APOE × age variable modulation of cognition was mediated by (1)H-MRS metabolites.nnnCONCLUSIONSnIn a healthy aging normal population, choline/creatine and myo-inositol/creatine ratios were significantly increased in APOE E4 carriers, suggesting the presence of neuroinflammatory processes and greater membrane turnover in older carriers. Structural equation modeling analysis confirmed these possible neurodegenerative markers and also indicated the mediator role of these metabolites on cognitive performance among older APOE E4 carriers.

Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways

BackgroundExpression of active c-Abl in adult mouse forebrain neurons in the AblPP/tTA mice resulted in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocytosis. In contrast, expression of constitutively active Arg (Abl-related gene) in mouse forebrain neurons (ArgPP/tTA mice) caused no detectable neuronal loss or gliosis, although protein expression and kinase activity were at similar levels to those in the AblPP/tTA mice.MethodsTo begin to elucidate the mechanism of c-Abl-induced neuronal loss and gliosis, gene expression analysis of AblPP/tTA mouse forebrain prior to development of overt pathology was performed. Selected results from gene expression studies were validated with quantitative reverse transcription PCR , immunoblotting and bromodeoxyuridine (BrdU) labeling, and by immunocytochemistry.ResultsTwo of the top pathways upregulated in AblPP/tTA mice with c-Abl expression for 2 weeks were cell cycle and interferon signaling. However, only the expression of interferon signaling pathway genes remained elevated at 4 weeks of c-Abl induction. BrdU incorporation studies confirm that, while the cell cycle pathway is upregulated in AblPP/tTA mice at 2 weeks of c-Abl induction, the anatomical localization of the pathway is not consistent with previous pathology seen in the AblPP/tTA mice. Increased expression and activation of STAT1, a known component of interferon signaling and interferon-induced neuronal excitotoxicity, is an early consequence of c-Abl activation in AblPP/tTA mice and occurs in the CA1 region of the hippocampus, the same region that goes on to develop severe neurodegenerative pathology and neuroinflammation. Interestingly, no upregulation of gene expression of interferons themselves was detected.ConclusionsOur data suggest that the interferon signaling pathway may play a role in the pathologic processes caused by c-Abl expression in neurons, and that the AblPP/tTA mouse may be an excellent model for studying sterile inflammation and the effects of interferon signaling in the brain.

Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease.

BACKGROUNDnThe earliest stage of preclinical Alzheimers disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood.nnnOBJECTIVEnTo examine dynamic interrelationships between Aβ42 and tau in preclinical AD.nnnMETHODSnWe followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (nu200a=u200a15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (nu200a=u200a14); and 3) Aβ42 levels consistently abnormal (nu200a=u200a18).nnnRESULTSnIn the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (pu200a=u200a0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rhou200a=u200a-0.60; pu200a=u200a0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2u200a=u200a0.47, pu200a=u200a0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (pu200a< u200a0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau.nnnCONCLUSIONSnThe evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.