Educational disparities in brain health and dementia across Latin America and the United States.

BACKGROUND: Education influences brain health and dementia. However, its impact across regions, specifically Latin America (LA) and the United States (US), is unknown. METHODS: A total of 1412 participants comprising controls, patients with Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) from LA and the US were included. We studied the association of education with brain volume and functional connectivity while controlling for imaging quality and variability, age, sex, total intracranial volume (TIV), and recording type. RESULTS: Education influenced brain measures, explaining 24%-98% of the geographical differences. The educational disparities between LA and the US were associated with gray matter volume and connectivity variations, especially in LA and AD patients. Education emerged as a critical factor in classifying aging and dementia across regions. DISCUSSION: The results underscore the impact of education on brain structure and function in LA, highlighting the importance of incorporating educational factors into diagnosing, care, and prevention, and emphasizing the need for global diversity in research. HIGHLIGHTS: Lower education was linked to reduced brain volume and connectivity in healthy controls (HCs), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). Latin American cohorts have lower educational levels compared to the those in the United States. Educational disparities majorly drive brain health differences between regions. Educational differences were significant in both conditions, but more in AD than FTLD. Education stands as a critical factor in classifying aging and dementia across regions.

Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease.

Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aß) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimer's disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Aß pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest.

Impact of the NGF maturation and degradation pathway on the cortical cholinergic system phenotype.

Cortical cholinergic atrophy plays a significant role in the cognitive loss seen with aging and in Alzheimer's disease (AD), but the mechanisms leading to it remain unresolved. Nerve growth factor (NGF) is the neurotrophin responsible for the phenotypic maintenance of basal forebrain cholinergic neurons in the mature and fully differentiated CNS. In consequence, its implication in cholinergic atrophy has been suspected; however, no mechanistic explanation has been provided. We have previously shown that the precursor of NGF (proNGF) is cleaved extracellularly by plasmin to form mature NGF (mNGF) and that mNGF is degraded by matrix metalloproteinase 9. Using cognitive-behavioral tests, Western blotting, and confocal and electron microscopy, this study demonstrates that a pharmacologically induced chronic failure in extracellular NGF maturation leads to a reduction in mNGF levels, proNGF accumulation, cholinergic degeneration, and cognitive impairment in rats. It also shows that inhibiting NGF degradation increases endogenous levels of the mature neurotrophin and increases the density of cortical cholinergic boutons. Together, the data point to a mechanism explaining cholinergic loss in neurodegenerative conditions such as AD and provide a potential therapeutic target for the protection or restoration of this CNS transmitter system in aging and AD.

Classification of Alzheimer's disease and frontotemporal dementia using routine clinical and cognitive measures across multicentric underrepresented samples: A cross sectional observational study.

Background: Global brain health initiatives call for improving methods for the diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD) in underrepresented populations. However, diagnostic procedures in upper-middle-income countries (UMICs) and lower-middle income countries (LMICs), such as Latin American countries (LAC), face multiple challenges. These include the heterogeneity in diagnostic methods, lack of clinical harmonisation, and limited access to biomarkers. Methods: This cross-sectional observational study aimed to identify the best combination of predictors to discriminate between AD and FTD using demographic, clinical and cognitive data among 1794 participants [904 diagnosed with AD, 282 diagnosed with FTD, and 606 healthy controls (HCs)] collected in 11 clinical centres across five LAC (ReDLat cohort). Findings: A fully automated computational approach included classical statistical methods, support vector machine procedures, and machine learning techniques (random forest and sequential feature selection procedures). Results demonstrated an accurate classification of patients with AD and FTD and HCs. A machine learning model produced the best values to differentiate AD from FTD patients with an accuracy = 0.91. The top features included social cognition, neuropsychiatric symptoms, executive functioning performance, and cognitive screening; with secondary contributions from age, educational attainment, and sex. Interpretation: Results demonstrate that data-driven techniques applied in archival clinical datasets could enhance diagnostic procedures in regions with limited resources. These results also suggest specific fine-grained cognitive and behavioural measures may aid in the diagnosis of AD and FTD in LAC. Moreover, our results highlight an opportunity for harmonisation of clinical tools for dementia diagnosis in the region. Funding: This work was supported by the Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat), funded by NIA/NIH (R01AG057234), Alzheimer's Association (SG-20-725707-ReDLat), Rainwater Foundation, Takeda (CW2680521), Global Brain Health Institute; as well as CONICET; FONCYT-PICT (2017-1818, 2017-1820); PIIECC, Facultad de Humanidades, Usach; Sistema General de Regalías de Colombia (BPIN2018000100059), Universidad del Valle (CI 5316); ANID/FONDECYT Regular (1210195, 1210176, 1210176); ANID/FONDAP (15150012); ANID/PIA/ANILLOS ACT210096; and Alzheimer's Association GBHI ALZ UK-22-865742.

Engagement of the PFC in consolidation and recall of recent spatial memory.

The standard model of system consolidation proposes that memories are initially hippocampus dependent and become hippocampus independent over time. Previous studies have demonstrated the involvement of the medial prefrontal cortex (mPFC) in the retrieval of remote memories. The transformations required to make a memory undergo system's consolidation are thought to require synaptic plasticity. In this study, we investigated the participation of the mitogen-activated protein kinase (MAPK)/ERK pathway in acquisition, memory consolidation, and recent memory recall of the Morris water maze (MWM) task using a 1-d training protocol. To this end, bilateral injections of the MEK inhibitor U0126 into the rat mPFC were performed. The injection of the MEK inhibitor in the mPFC did not affect the acquisition of the MWM. However, MEK inhibitor resulted in impairments on recent memory retrieval either when applied at the end of the learning phase (memory consolidation) or prior to the retention test. The results strongly support the concept that recently acquired and consolidated spatial memories require the mPFC, and that local activation of the MAPK/ERK pathway in the mPFC is necessary for the consolidation and recall of recent memories.

Liver X Receptor Activation with an Intranasal Polymer Therapeutic Prevents Cognitive Decline without Altering Lipid Levels.

The progressive accumulation of amyloid-beta (Aß) in specific areas of the brain is a common prelude to late-onset of Alzheimer's disease (AD). Although activation of liver X receptors (LXR) with agonists decreases Aß levels and ameliorates contextual memory deficit, concomitant hypercholesterolemia/hypertriglyceridemia limits their clinical application. DMHCA (N,N-dimethyl-3ß-hydroxycholenamide) is an LXR partial agonist that, despite inducing the expression of apolipoprotein E (main responsible of Aß drainage from the brain) without increasing cholesterol/triglyceride levels, shows nil activity in vivo because of a low solubility and inability to cross the blood brain barrier. Herein, we describe a polymer therapeutic for the delivery of DMHCA. The covalent incorporation of DMHCA into a PEG-dendritic scaffold via carboxylate esters produces an amphiphilic copolymer that efficiently self-assembles into nanometric micelles that exert a biological effect in primary cultures of the central nervous system (CNS) and experimental animals using the intranasal route. After CNS biodistribution and effective doses of DMHCA micelles were determined in nontransgenic mice, a transgenic AD-like mouse model of cerebral amyloidosis was treated with the micelles for 21 days. The benefits of the treatment included prevention of memory deterioration and a significant reduction of hippocampal Aß oligomers without affecting plasma lipid levels. These results represent a proof of principle for further clinical developments of DMHCA delivery systems.

The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat): Driving Multicentric Research and Implementation Science.

Dementia is becoming increasingly prevalent in Latin America, contrasting with stable or declining rates in North America and Europe. This scenario places unprecedented clinical, social, and economic burden upon patients, families, and health systems. The challenges prove particularly pressing for conditions with highly specific diagnostic and management demands, such as frontotemporal dementia. Here we introduce a research and networking initiative designed to tackle these ensuing hurdles, the Multi-partner consortium to expand dementia research in Latin America (ReDLat). First, we present ReDLat's regional research framework, aimed at identifying the unique genetic, social, and economic factors driving the presentation of frontotemporal dementia and Alzheimer's disease in Latin America relative to the US. We describe ongoing ReDLat studies in various fields and ongoing research extensions. Then, we introduce actions coordinated by ReDLat and the Latin America and Caribbean Consortium on Dementia (LAC-CD) to develop culturally appropriate diagnostic tools, regional visibility and capacity building, diplomatic coordination in local priority areas, and a knowledge-to-action framework toward a regional action plan. Together, these research and networking initiatives will help to establish strong cross-national bonds, support the implementation of regional dementia plans, enhance health systems' infrastructure, and increase translational research collaborations across the continent.

Statistical differences resulting from selection of stable reference genes after hypoxia and hypothermia in the neonatal rat brain.

Real-time reverse transcription PCR (qPCR) normalized to an internal reference gene (RG), is a frequently used method for quantifying gene expression changes in neuroscience. Although RG expression is assumed to be constant independent of physiological or experimental conditions, several studies have shown that commonly used RGs are not expressed stably. The use of unstable RGs has a profound effect on the conclusions drawn from studies on gene expression, and almost universally results in spurious estimation of target gene expression. Approaches aimed at selecting and validating RGs often make use of different statistical methods, which may lead to conflicting results. Based on published RG validation studies involving hypoxia the present study evaluates the expression of 5 candidate RGs (Actb, Pgk1, Sdha, Gapdh, Rnu6b) as a function of hypoxia exposure and hypothermic treatment in the neonatal rat cerebral cortex-in order to identify RGs that are stably expressed under these experimental conditions-using several statistical approaches that have been proposed to validate RGs. In doing so, we first analyzed RG ranking stability proposed by several widely used statistical methods and related tools, i.e. the Coefficient of Variation (CV) analysis, GeNorm, NormFinder, BestKeeper, and the ΔCt method. Using the Geometric mean rank, Pgk1 was identified as the most stable gene. Subsequently, we compared RG expression patterns between the various experimental groups. We found that these statistical methods, next to producing different rankings per se, all ranked RGs displaying significant differences in expression levels between groups as the most stable RG. As a consequence, when assessing the impact of RG selection on target gene expression quantification, substantial differences in target gene expression profiles were observed. Altogether, by assessing mRNA expression profiles within the neonatal rat brain cortex in hypoxia and hypothermia as a showcase, this study underlines the importance of further validating RGs for each individual experimental paradigm, considering the limitations of the statistical methods used for this aim.

Clinical Implications of Epigenetic Dysregulation in Perinatal Hypoxic-Ischemic Brain Damage.

Placental and fetal hypoxia caused by perinatal hypoxic-ischemic events are major causes of stillbirth, neonatal morbidity, and long-term neurological sequelae among surviving neonates. Brain hypoxia and associated pathological processes such as excitotoxicity, apoptosis, necrosis, and inflammation, are associated with lasting disruptions in epigenetic control of gene expression contributing to neurological dysfunction. Recent studies have pointed to DNA (de)methylation, histone modifications, and non-coding RNAs as crucial components of hypoxic-ischemic encephalopathy (HIE). The understanding of epigenetic dysregulation in HIE is essential in the development of new clinical interventions for perinatal HIE. Here, we summarize our current understanding of epigenetic mechanisms underlying the molecular pathology of HI brain damage and its clinical implications in terms of new diagnostic, prognostic, and therapeutic tools.

Amyloid beta-induced nerve growth factor dysmetabolism in Alzheimer disease.

We previously reported that the precursor form of nerve growth factor (pro-NGF) and not mature NGF is liberated in the CNS in an activity-dependent manner, and that its maturation and degradation occur in the extracellular space by the coordinated action of proteases.Here, we present evidence of diminished conversion of pro-NGF to its mature form and of greater NGF degradation in Alzheimer disease (AD) brain samples compared with controls. These alterations of the NGF metabolic pathway likely resulted in the increased pro-NGF levels. The pro-NGF was largely in a peroxynitrited form in the AD samples. Intrahippocampal injection of amyloid-beta oligomers provoked similar upregulation of pro-NGF in naive rats that was accompanied by evidence of microglial activation (CD40), increased levels of inducible nitric oxide synthase, and increased activity of the NGF-degrading enzyme matrix metalloproteinase 9. The elevated inducible nitric oxide synthase provoked the generation of biologically inactive, peroxynitrite-modified pro-NGF in amyloid-beta oligomer-injected rats. These parameters were corrected by minocycline treatment. Minocycline also diminished altered matrix metalloproteinase 9, inducible nitric oxide synthase, and microglial activation (CD40); improved cognitive behavior; and normalized pro-NGF levels in a transgenic mouse AD model. The effects of amyloid-beta amyloid CNS burden on NGF metabolism may explain the paradoxical upregulation of pro-NGF in AD accompanied by atrophy of forebrain cholinergic neurons.

Aptamers as Diagnostic Tools in Cancer.

Cancer is the second leading cause of death worldwide. Researchers have been working hard on investigating not only improved therapeutics but also on early detection methods, both critical to increasing treatment efficacy, and developing methods for disease prevention. The use of nucleic acids, or aptamers, has emerged as more specific and accurate cancer diagnostic and therapeutic tools. Aptamers are single-stranded DNA or RNA molecules that recognize specific targets based on unique three-dimensional conformations. Despite the fact aptamer development has been mainly restricted to laboratory settings, the unique attributes of these molecules suggest their high potential for clinical advances in cancer detection. Aptamers can be selected for a wide range of targets, and also linked with an extensive variety of diagnostic agents, via physical or chemical conjugation, to improve previously-established detection methods or to be used as novel biosensors for cancer diagnosis. Consequently, herein we review the principal considerations and recent updates in cancer detection and imaging through aptamer-based molecules.

Long-lasting rescue of age-associated deficits in cognition and the CNS cholinergic phenotype by a partial agonist peptidomimetic ligand of TrkA.

Previously, we developed a proteolytically stable small molecule peptidomimetic termed D3 as a selective ligand of the extracellular domain of the TrkA receptor for the NGF. Ex vivo D3 was defined as a selective, partial TrkA agonist. Here, the in vivo efficacy of D3 as a potential therapeutic for cholinergic neurons was tested in cognitively impaired aged rats, and we compared the consequence of partial TrkA activation (D3) versus full TrkA/p75 activation (NGF). We show that in vivo D3 binds to TrkA receptors and affords a significant and long-lived phenotypic rescue of the cholinergic phenotype both in the cortex and in the nucleus basalis. The cholinergic rescue was selective and correlates with a significant improvement of memory/learning in cognitively impaired aged rats. The effects of the synthetic ligand D3 and the natural ligand NGF were comparable. Small, proteolytically stable ligands with selective agonistic activity at a growth factor receptor may have therapeutic potential for neurodegenerative disorders.

Cortical peroxynitration of nerve growth factor in aged and cognitively impaired rats.

Basal forebrain cholinergic neurons (BFCN), a system involved in learning and memory processes, are highly dependent on a continuous supply of biologically active nerve growth factor (NGF). Age-related cholinergic atrophy and cell loss in normal brains is apparently not complemented by reductions in the levels of NGF as could be expected. In the present work, cortical proNGF/NGF were immunoprecipitated from cortical brain homogenates from young and aged and behaviorally characterized rats and resolved with antinitrotyrosine antibodies to reveal nitration of tyrosine residues in proteins. Cortical proNGF in aged and cognitively impaired rats was found to be a target for peroxynitrite-mediated oxidative damage with correlative impact on decrease in choline acetyltransferase activity. These studies provide evidence for oxidative stress damage of NGF molecules in the cerebral cortex of cognitively impaired aged rats as previously shown in AD human brains.

Intracellular Aß-oligomers and early inflammation in a model of Alzheimer's disease.

Lifelong use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to diminish the incidence of Alzheimer's disease (AD), suggesting a key role of inflammation in early stages of the pathology. While amyloid plaque-associated inflammation has been extensively studied in human and animal models, little is known about the inflammatory process prior to plaque deposition, i.e., in preclinical stages of AD. In this study we investigated microglial and neuronal inflammatory markers in preplaque transgenic McGill-Thy1-APP mice. We found evidence that prior to plaque deposition classical markers of microglial activation such as major histocompatibility complex class II (MHC-II), inducible nitric oxide synthase (i-NOS), and CD40 are already upregulated in the hippocampus of transgenic mice. Microglial cells from transgenic mice in the preplaque stage displayed intermediately activated morphology and appeared to be recruited toward intracellular amyloid-ß peptide (Aß)-oligomer burdened neurons. The inducible, neuron-specific cyclooxygenase 2 (COX-2) enzyme was found to be upregulated and specifically expressed by neurons in close relationship with Aß-bearing cells, at this early stage of the AD-like pathology. Our study suggests that neuroinflammation might be one of the earliest pathological responses to intracellular accumulation of Aß-oligomers.

Cholinergic involvement in Alzheimer's disease. A link with NGF maturation and degradation.

Basal forebrain cholinergic neurons are highly dependent on nerve growth factor (NGF) supply for the maintenance of their cholinergic phenotype as well as their cholinergic synaptic integrity. The precursor form of NGF, proNGF, abounds in the CNS and is highly elevated in Alzheimer's disease. In order to obtain a deeper understanding of the NGF biology in the CNS, we have performed a series of ex vivo and in vivo investigations to elucidate the mechanisms of release, maturation and degradation of this neurotrophin. In this short review, we describe this NGF metabolic pathway, its significance for the maintenance of basal cholinergic neurons, and its dysregulation in Alzheimer's disease. We are proposing that the conversion of proNGF to mature NGF occurs in the extracellular space by the coordinated action of zymogens, convertases, and endogenous regulators, which are released in the extracellular space in an activity-dependent fashion. We further discuss our findings of a diminished conversion of the NGF precursor molecule to its mature form in Alzheimer's disease as well as an augmented degradation of mature NGF. These combined effects on NGF metabolism would explain the well-known cholinergic atrophy found in Alzheimer's disease and would offer new therapeutic opportunities aimed at correcting the NGF dysmetabolism along with Abeta-induced inflammatory responses.

Increased matrix metalloproteinase 9 activity in mild cognitive impairment.

Nerve growth factor (NGF)-dependent cholinergic basal forebrain neurons degenerate during the progression of Alzheimer disease (AD). Elevated proNGF and reduced levels of the TrkA high-affinity NGF receptor occur in prodromal and advanced stages of AD. We recently described a protease cascade responsible for the conversion of proNGF to mature NGF (mNGF) in which matrix metalloproteinase 9 (MMP-9) degrades mNGF in the extracellular space. To determine whether this proteolytic cascade is altered during the progression of AD, we examined human frontal and parietal cortex tissues from aged subjects with a clinical diagnosis of AD, mild cognitive impairment, or no cognitive impairment. The analysis demonstrated greater MMP-9 activity in both AD and mild cognitive impairment compared with no cognitive impairment brain samples (p < 0.01), which supports the notion that a metabolic failure in the NGF-maturation/degradation pathway may be associated with an exacerbated degradation of mNGF in the cerebral cortex in early AD. Moreover, there were inverse correlations between Global Cognitive Score and Mini-Mental State Examination score and MMP-9 activity. These findings suggest that a reduction in mNGF as a consequence of MMP-9-mediated degradation may in part underlie the pathogenesis of cognitive deficits in mild cognitive impairment and AD.

The failure in NGF maturation and its increased degradation as the probable cause for the vulnerability of cholinergic neurons in Alzheimer's disease.

This short review discusses the arguments to consider the dismetabolism of the pathway responsible for both the maturation and degradation of NGF as the culprit of vulnerability of the forebrain cholinergic system to the Alzheimer's disease neuropathology. This summary includes information regarding a novel metabolic cascade converting Pro-NGF to mature NGF in the extracellular space and its ultimate degradation by a metalloprotease. It also describes how this pathway is altered in Alzheimer's disease with the consequential CNS accumulation of proNGF and impairment in the formation of NGF along with increased degradation of this key trophic factor. This metabolic scenario in Alzheimer's disease should result in the failure of NGF trophic support to forebrain cholinergic neurons and thus explaining the vulnerability of these neurons in this neurodegenerative condition.

Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade.

In this report, we provide direct demonstration that the neurotrophin nerve growth factor (NGF) is released in the extracellular space in an activity-dependent manner in its precursor form (proNGF) and that it is in this compartment that its maturation and degradation takes place because of the coordinated release and the action of proenzymes and enzyme regulators. This converting protease cascade and its endogenous regulators (including tissue plasminogen activator, plasminogen, neuroserpin, precursor matrix metalloproteinase 9, and tissue inhibitor metalloproteinase 1) are colocalized in neurons of the cerebral cortex and released upon neuronal stimulation. We also provide evidence that this mechanism operates in in vivo conditions, as the CNS application of inhibitors of converting and degrading enzymes lead to dramatic alterations in the tissue levels of either precursor NGF or mature NGF. Pathological alterations of this cascade in the CNS might cause or contribute to a lack of proper neuronal trophic support in conditions such as cerebral ischemia, seizure and Alzheimer's disease or, conversely, to excessive local production of neurotrophins as reported in inflammatory arthritis pain.