Early Biomarker For Alzheimer's Disease Research Articles

Transcriptomic Analysis of Alzheimer's Disease Pathways in a Pakistani Population.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that is most prevalent in elderly individuals, especially in developed countries, and its prevalence is now increasing in developing countries like Pakistan. Our goal was to characterize key genes and their levels of expression and related molecular transcriptome networks associated with AD pathogenesis in a pilot case-control study in a Pakistani population. To obtain the spectrum of molecular networks associated with pathogenesis in AD patients in Pakistan (comparing cases and controls), we used high-throughput qRT-PCR (TaqMan Low-Density Array; n = 33 subjects) coupled with Affymetrix Arrays (n = 8) and Ingenuity Pathway Analysis (IPA) to identify signature genes associated with Amyloid processing and disease pathways. We confirmed 16 differentially expressed AD-related genes, including maximum fold changes observed in CAPNS2 and CAPN1. The global gene expression study observed that 61% and 39% of genes were significantly (p-value 0.05) up- and downregulated, respectively, in AD patients compared to healthy controls. The key pathways include, e.g., Amyloid Processing, Neuroinflammation Signaling, and ErbB4 Signaling. The top-scoring networks in Diseases and Disorders Development were Neurological Disease, Organismal Injury and Abnormalities, and Psychological Disorders. Our pilot study offers a non-invasive and efficient way of investigating gene expression patterns by combining TLDA and global gene expression method in AD patients by utilizing whole blood. This provides valuable insights into the expression status of genes related to Amyloid Processing, which could play potential role in future studies to identify sensitive, early biomarkers of AD in general.

Beyond CSF and Neuroimaging Assessment: Evaluating Plasma miR-145-5p as a Potential Biomarker for Mild Cognitive Impairment and Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia. New strategies for the early detection of MCI and sporadic AD are crucial for developing effective treatment options. Current techniques used for diagnosis of AD are invasive and/or expensive, so they are not suitable for population screening. Cerebrospinal fluid (CSF) biomarkers such as amyloid β1-42 (Aβ1-42), total tau (T-tau), and phosphorylated tau181 (P-tau181) levels are core biomarkers for early diagnosis of AD. Several studies have proposed the use of blood-circulating microRNAs (miRNAs) as potential novel early biomarkers for AD. We therefore applied a novel approach to identify blood-circulating miRNAs associated with CSF biomarkers and explored the potential of these miRNAs as biomarkers of AD. In total, 112 subjects consisting of 28 dementia due to AD cases, 63 MCI due to AD cases, and 21 cognitively healthy controls were included. We identified seven Aβ1-42-associated plasma miRNAs, six P-tau181-associated plasma miRNAs, and nine Aβ1-42-associated serum miRNAs. These miRNAs were involved in AD-relevant biological processes, such as PI3K/AKT signaling. Based on this signaling pathway, we constructed an miRNA-gene target network, wherein miR-145-5p has been identified as a hub. Furthermore, we showed that miR-145-5p performs best in the prediction of both AD and MCI. Moreover, miR-145-5p also improved the prediction performance of the mini-mental state examination (MMSE) score. The performance of this miRNA was validated using different datasets including an RT-qPCR dataset from plasma samples of 23 MCI cases and 30 age-matched controls. These findings indicate that blood-circulating miRNAs that are associated with CSF biomarkers levels and specifically plasma miR-145-5p alone or combined with the MMSE score can potentially be used as noninvasive biomarkers for AD or MCI screening in the general population, although studies in other AD cohorts are necessary for further validation.

Functional measures and AD biomarkers among Hispanic and White non-Hispanic older adults.

Poorer baseline functioning is associated with long-term cognitive decline among Hispanic older adults, but little is known about associations of these factors with Alzheimer's disease (AD) neuroimaging biomarkers. A total of 461 Hispanic and White non-Hispanic (NHW) older adults who are cognitively normal (n=76), had impaired cognition without mild cognitive impairment (MCI) (n=41), or carried a diagnosis of MCI (n=253) or dementia (n=91) completed neuropsychological and functional assessment, genetic testing, and brain magnetic resonance imaging (MRI). Structural equation modeling (SEM) was used to examine predictive associations between functional and cognitive measures of AD neuroimaging biomarkers. MRI volumes significantly predicted functional limitations in both groups. Sex and amyloid load significantly predicted functional limitations among the Hispanic group only. Years of education and MRI regional volume were the strongest predictors of cognition among both groups. Results indicate that functional performance is associated with early AD biomarkers among Hispanic older adults. Clinical implications are discussed. The current study addresses health disparities in Alzheimer's disease (AD) and related dementia assessment among Hispanics by identifying measures sensitive to early AD biomarkers.Associations of functional measures with AD genetic and neuroimaging biomarkers revealed that similarities in these associations exist between Hispanic and White non-Hispanic individuals, but biological sex and amyloid load significantly predicted functional limitations among the Hispanic group only.These results have clinical implications for physicians who treat Hispanic AD patients and indicate that when compared to traditional diagnostic assessments, functional assessments may better aid in AD diagnostic precision among Hispanics.

Probing latent brain dynamics in Alzheimer's disease via recurrent neural network.

The impairment of cognitive function in Alzheimer's disease (AD) is clearly correlated to abnormal changes in cortical rhythm. However, the mechanisms underlying this correlation are still poorly understood. Here, we investigate how network structure and dynamical characteristics alter their abnormal changes in cortical rhythm. To that end, biological data of AD and normal participates are collected. By extracting the energy characteristics of different sub-bands in EEG signals, we find that the rhythm of AD patients is special particularly in theta and alpha bands. The cortical rhythm of normal state is mainly at alpha band, while that of AD state shift to the theta band. Furthermore, recurrent neural network (RNN) is trained to explore the rhythm formation and transformation between two neural states from the perspective view of neurocomputation. It is found that the neural coupling strength decreases significantly under AD state when compared with normal state, which weakens the ability of information transmission in AD state. Besides, the low-dimensional properties of RNN are obtained. By analyzing the relationship between the cortical rhythm transition and the low-dimensional trajectory, it is concluded that the low-dimensional trajectory update is slower and the communication cost is higher in AD state, which explains the abnormal synchronization of AD brain network. Our work reveals the causes for the formation of abnormal brain synchronous functional network status, which may expand our understanding of the mechanism of cognitive impairment in AD and provide an EEG biomarker for early AD.

Hippocampal functional connectivity across age in an App knock-in mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. The early processes of AD, however, are not fully understood and likely begin years before symptoms manifest. Importantly, disruption of the default mode network, including the hippocampus, has been implicated in AD. To examine the role of functional network connectivity changes in the early stages of AD, we performed resting-state functional magnetic resonance imaging (rs-fMRI) using a mouse model harboring three familial AD mutations (App NL-G-F/NL-G-F knock-in, APPKI) in female mice in early, middle, and late age groups. The interhemispheric and intrahemispheric functional connectivity (FC) of the hippocampus was modeled across age. We observed higher interhemispheric functional connectivity (FC) in the hippocampus across age. This was reduced, however, in APPKI mice in later age. Further, we observed loss of hemispheric asymmetry in FC in APPKI mice. Together, this suggests that there are early changes in hippocampal FC prior to heavy onset of amyloid β plaques, and which may be clinically relevant as an early biomarker of AD.

Association of spermidine plasma levels with brain aging in a population-based study.

Supplementation with spermidine may support healthy aging, but elevated spermidine tissue levels were shown to be an indicator of Alzheimer's disease (AD). Data from 659 participants (age range: 21-81 years) of the population-based Study of Health in Pomerania TREND were included. We investigated the association between spermidine plasma levels and markers of brain aging (hippocampal volume, AD score, global cortical thickness [CT], and white matter hyperintensities [WMH]). Higher spermidine levels were significantly associated with lower hippocampal volume (ß=-0.076; 95% confidence interval [CI]: -0.13 to -0.02; q =0.026), higher AD score (ß=0.118; 95% CI: 0.05 to 0.19; q =0.006), lower global CT (ß=-0.104; 95% CI: -0.17 to -0.04; q =0.014), but not WMH volume. Sensitivity analysis revealed no substantial changes after excluding participants with cancer, depression, or hemolysis. Elevated spermidine plasma levels are associated with advanced brain aging and might serve as potential early biomarker for AD and vascular brain pathology.

Lipids as Early and Minimally Invasive Biomarkers for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Specifically, typical late-onset AD is a sporadic form with a complex etiology that affects over 90% of patients. The current gold standard for AD diagnosis is based on the determination of amyloid status by analyzing cerebrospinal fluid samples or brain positron emission tomography. These procedures can be used widely as they have several disadvantages (expensive, invasive). As an alternative, blood metabolites have recently emerged as promising AD biomarkers. Small molecules that cross the compromised AD blood-brain barrier could be determined in plasma to improve clinical AD diagnosis at early stages through minimally invasive techniques. Specifically, lipids could play an important role in AD since the brain has a high lipid content, and they are present ubiquitously inside amyloid plaques. Therefore, a systematic review was performed with the aim of identifying blood lipid metabolites as potential early AD biomarkers. In conclusion, some lipid families (fatty acids, glycerolipids, glycerophospholipids, sphingolipids, lipid peroxidation compounds) have shown impaired levels at early AD stages. Ceramide levels were significantly higher in AD subjects, and polyunsaturated fatty acids levels were significantly lower in AD. Also, high arachidonic acid levels were found in AD patients in contrast to low sphingomyelin levels. Consequently, these lipid biomarkers could be used for minimally invasive and early AD clinical diagnosis.

Rapid olfactory decline during aging predicts dementia and GMV loss in AD brain regions.

Longitudinal multivariable analyses are needed to determine if the rate of olfactory decline during normal cognition predicts subsequent Alzheimer's disease (AD) diagnoses and brain dysmorphology. Older adults (n= 515) were assessed annually for odor identification, cognitive function and dementia clinical diagnosis (max follow-up 18 years). Regional gray matter volumes (GMV) were quantified (3T MRI) in a cross-sectional subsample (n= 121). Regression models were adjusted for APOE-ε4 genotype, dementia risk factors and demographics. Faster olfactory decline during periods of normal cognition predicted higher incidence of subsequent MCI or dementia (OR 1.89, 95% CI: 1.26, 2.90, p< 0.01; comparable to carrying an APOE-ε4 allele) and smaller GMV in AD and olfactory regions (β= -0.11, 95% CI -0.21, -0.00). Rapid olfactory decline during normal cognition, using repeated olfactory measurement, predicted subsequent cognitive impairment, dementia, and smaller GMVs, highlighting its potential as a simple biomarker for early AD detection. Rate of olfactory decline was calculated from olfactory testing over ≥3 time points. Rapid olfactory decline predicted impaired cognition and higher risk of dementia. Neurodegeneration on 3T magnetic resonance imaging was identical in those with olfactory decline and Alzheimer's disease.

Potential biomarkers of early diagnosis of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the brain, in which there are cognitive and behavioral disorders, but also visual impairment can occur. Deposits of beta-amyloid (Aβ) were also found in the retina of AD patients. At the same time, primary open-angle glaucoma (POAG) occupies the first place among geronto-ophthalmic pathologies in patients with AD. POAG, like AD, is a neurodegenerative disease. AD and POAG have common symptoms, and therefore several common principles for their early diagnosis can be developed. Therefore, a promising direction is the search for biomarkers for the early detection of AD and POAG. Currently, the diagnosis of early AD biomarkers in cerebrospinal fluid and biomarkers in the brain (imaging of amyloid plaques and tau positron emission tomography) are well studied, while data in literature on using these biomarkers in patients with POAG is scarce. However, the above diagnostic methods are not considered in routine clinical practice due to their invasiveness and high cost. There is a growing need for conventional, affordable biomarkers for AD and POAG, as it is necessary to start treatment of prodromal conditions from symptoms to onset of symptoms. In this connection, biomarkers such as Aβ and tau protein in blood serum and plasma are actively evaluated in patients with AD. In patients with POAG, there is no published data on studies of these biomarkers, which requires scientific research. Many authors discover the role of sirtuins (SIRT) in aging and age-related diseases, such as AD, glaucoma, age-related macular degeneration, and others. Possibly, SIRT could become potential biomarkers of neurodegenerative diseases.

White matter microstructural damage as an early sign of subjective cognitive decline

AbstractBackgroundSubjective cognitive decline (SCD) is considered a preclinical state of Alzheimer's disease (AD) and may represent a more advanced preclinical status than amnestic mild cognitive impairment (aMCI). Our aim was to explore changes in the white matter (WM) microstructure and their correlation with cognitive function in these AD‐spectrum patients.MethodDiffusion tensor images from 43 individuals with normal cognition (NC), 38 SCD patients and 36 aMCI patients were compared using an atlas‐based segmentation strategy. The correlation between diffusion parameters and cognitive function was further analysed.ResultThe anatomical pattern of WM impairment was generally similar between SCD and aMCI patients. However, aMCI patients showed significantly lower fractional anisotropy (FA) values in corpus callosum (forceps major (Fma) and forceps minor (Fmi)), as well as significantly increased mean diffusivity (MD) in the bilateral anterior thalamic radiation (ATR), left corticospinal tract (CST. L), Fmi, left Cingulum (cingulate gyrus) (CgC. L), left cingulum (hippocampus) (CgH. L), and left inferior fronto‐occipital fasciculus (IFO. L), than those of SCD subjects, indicating a disruption in WM microstructural integrity in the aMCI. Individuals with microstructural disruption in Fmi, CgC. L and CgH. L tracts performed worse in general cognition and memory function tests, as indicated by line regression analysis.ConclusionSCD individuals had extensive WM microstructural damage in a pattern similar to that seen in aMCI, although presenting a cognitive performance comparable to cognitively healthy individuals. Our results suggest that WM integrity might precede objectively measurable memory decline and may be a potential early biomarker for AD.

Comprehensive Proteomic Profiling of Urinary Exosomes and Identification of Potential Non-invasive Early Biomarkers of Alzheimer's Disease in 5XFAD Mouse Model.

BackgroundAlzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by irreversible progressive cognitive deficits. Identification of candidate biomarkers, before amyloid-β-plaque deposition occurs, is therefore of great importance for early intervention of AD.ObjectiveTo investigate the potential non-invasive early biomarkers of AD in 5XFAD mouse model, we investigate the proteome of urinary exosomes present in 1-month-old (before amyloid-β accumulation) 5XFAD mouse models and their littermate controls. Another two groups of 2 and 6 months-old urinary samples were collected for monitoring the dynamic change of target proteins during AD progression.MethodsProteomic, bioinformatics analysis, multiple reaction monitoring (MRM), western blotting (WB) or ELISA were performed for analyzing these urinary exosomes.ResultsA total of 316 proteins including 44 brain cell markers were identified using liquid chromatography tandem mass spectrometry. Importantly, 18 proteins were unique to the 5XFAD group. Eighty-eight proteins including 11 brain cell markers were differentially expressed. Twenty-two proteins were selected to be verified by WB. Furthermore, based on an independent set of 12 urinary exosomes samples, five in these proteins were further confirmed significant difference. Notably, Annexin 2 and Clusterin displayed significant decreased in AD model during the course detected by ELISA. AOAH, Clusterin, and Ly86 are also brain cell markers that were first reported differential expression in urinary exosomes of AD model.ConclusionOur data demonstrated that some urinary exosome proteins, especially Annexin 2 and Clusterin, as nanometer-sized particles, enable detection of differences before amyloid-β-plaque deposition in 5XFAD mouse model, which may present an ideal non-invasive source of biomarkers for prevention of AD.

Tip60 protects against amyloid-β-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegeneration

Alzheimer's disease (AD) is an age-related neurodegenerative disorder hallmarked by amyloid-β (Aβ) plaque accumulation, neuronal cell death, and cognitive deficits that worsen during disease progression. Histone acetylation dysregulation, caused by an imbalance between reduced histone acetyltransferases (HAT) Tip60 and increased histone deacetylase 2 (HDAC2) levels, can directly contribute to AD pathology. However, whether such AD-associated neuroepigenetic alterations occur in response to Aβ peptide production and can be protected against by increasing Tip60 levels over the course of neurodegenerative progression remains unknown. Here we profile Tip60 HAT/HDAC2 dynamics and transcriptome-wide changes across early and late stage AD pathology in the Drosophila brain produced solely by human amyloid-β42. We show that early Aβ42 induction leads to disruption of Tip60 HAT/HDAC2 balance during early neurodegenerative stages preceding Aβ plaque accumulation that persists into late AD stages. Correlative transcriptome-wide studies reveal alterations in biological processes we classified as transient (early-stage only), late-onset (late-stage only), and constant (both). Increasing Tip60 HAT levels in the Aβ42 fly brain protects against AD functional pathologies that include Aβ plaque accumulation, neural cell death, cognitive deficits, and shorter life-span. Strikingly, Tip60 protects against Aβ42-induced transcriptomic alterations via distinct mechanisms during early and late stages of neurodegeneration. Our findings reveal distinct modes of neuroepigenetic gene changes and Tip60 neuroprotection in early versus late stages in AD that can serve as early biomarkers for AD, and support the therapeutic potential of Tip60 over the course of AD progression.

Narrative Review of Sensory Changes as a Biomarker for Alzheimer's Disease.

Early recognition of Alzheimer's disease (AD) in the prodromal period has not been robust yet will be necessary if effective disease-modifying drugs are to be useful in preventing or delaying the condition. The objective of this narrative review was to describe the current, evidenced based understanding of alterations in sensory data as potential biomarkers for AD. Review of empirical studies that tested senses as biomarkers for AD and were published in English within the past 50 years was completed. Eighteen empirical studies were identified that met the strict criteria for inclusion, with 12 of these studies being related to the olfactory system. Two studies examined auditory, two examined vision, one examined proprioception, and one examined taste. Thus, only olfaction has been studied to any extent, leaving a clear gap in the literature for the use of other senses. A promising area of research has begun to be reported concerning differences in responses to pain stimuli in AD relative to cognitively normal subjects. Pain is not a single sense like the others but integrates several senses and may allow for use as an early biomarker for AD, as it integrates several brain areas and pathways. Unlike the other senses, simple devices can be used to measure changes in pain perception in cognitively normal adults with genetic predispositions for possible AD, making this potentially useful for clinicians in the future.

Alpha rhythm slowing in a modified thalamo-cortico-thalamic model related with Alzheimer's disease.

A decrease in alpha band power is defined as a hallmark of electroencephalogram (EEG) in Alzheimer’s disease (AD). This study devotes to understanding the neuronal correlates of alpha rhythm slowing associated with AD from the view of neurocomputation. Firstly, a modified computational model of thalamo-cortico-thalamic (TCT) circuitry is constructed by incorporating two important biologically plausible ingredients. One is the disinhibition property between different inhibitory interneurons in the cortical module. The other is the full relay function of thalamic relay nucleus (TCR) to the cortical module. Then, by decreasing synaptic connectivity parameters to mimic the neuropathological condition of synapse loss in AD, the correlation between neuronal synaptic behavior and abnormal alpha rhythm is simulated by means of power spectral analysis. The results indicate that these decreases of synaptic activity, i.e., not only the excitatory synaptic connections from TCR to fast inhibitory interneurons Cfte and from excitatory interneurons to pyramidal neurons Cpxe but also the inhibitory synaptic connections from fast inhibitory interneurons to slow inhibitory interneurons Clfi and from inhibitory interneurons to TCR Ctii, can significantly diminish the peak power density over the alpha band of the thalamic output, which implies that there is a slowing of alpha band. Furthermore, the underlying mechanism behind the alpha rhythmic changes is analyzed using nonlinear dynamical technique. The results reveal that decreases of Cfte, Cpxe, Clfi and Ctii can make the thalamic module transfer from a limit cycle mode to a point attractor mode, which may lead to the alpha rhythm slowing in the modified TCT model. We expect this work can be helpful in identifying early biomarkers of AD’s EEG and understanding potential pathogenesis of AD.

White Matter Microstructural Damage as an Early Sign of Subjective Cognitive Decline

Background and Objective: Subjective cognitive decline (SCD) is considered a preclinical state of Alzheimer’s disease (AD) and may represent a more advanced preclinical status than amnestic mild cognitive impairment (aMCI). Our aim was to explore changes in the white matter (WM) microstructure and their correlation with cognitive function in these AD-spectrum patients.Methods: Diffusion tensor images from 43 individuals with normal cognition (NC), 38 SCD patients, and 36 aMCI patients were compared using an atlas-based segmentation strategy. The correlation between diffusion parameters and cognitive function was further analyzed.Results: The anatomical pattern of WM impairment was generally similar between SCD and aMCI patients. However, aMCI patients showed significantly lower fractional anisotropy (i.e., corpus callosum forceps major and forceps minor) and increased mean diffusivity [i.e., bilateral anterior thalamic radiation (ATR), left corticospinal tract (CST), forceps minor, left cingulum (cingulate gyrus), left cingulum hippocampus, and left inferior fronto-occipital fasciculus (IFO)] in some tracts than did SCD subjects, indicating a disruption in WM microstructural integrity in the aMCI. Individuals with microstructural disruption in forceps minor, left cingulum (cingulate gyrus), and left cingulum hippocampus tracts performed worse in general cognition and memory function tests, as indicated by line regression analysis.Conclusion: SCD individuals had extensive WM microstructural damage in a pattern similar to that seen in aMCI, although presenting a cognitive performance comparable with that of cognitively healthy individuals. Our results suggest that WM integrity might precede objectively measurable memory decline and may be a potential early biomarker for AD.

MiR-409-5p as a Regulator of Neurite Growth Is Down Regulated in APP/PS1 Murine Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disease. Recent studies suggest that miRNA expression changes are associated with the development of AD. Our previous study showed that the expression level of miR-409-5p was stably downregulated in the early stage of APP/PS1 double transgenic mice model of AD. We now report that miR-409-5p impairs neurite outgrowth, decreases neuronal viability, and accelerates the progression of Aβ1–42-induced pathologies. In this study, we found that Aβ1–42 peptide significantly decreased the expression of miR-409-5p, which was consistent with the expression profile of miR-409-5p in the APP/PS1 mice cortexes. Plek was confirmed to be a potential regulatory target of miR-409-5p by luciferase assay and Western blotting. Overexpression of miR-409-5p has an obvious neurotoxicity in neuronal cell viability and differentiation, whereas Plek overexpression could partially rescue neurite outgrowth from this toxicity. Some cytoskeleton regulatory proteins have been found to be related to AD pathogenesis. Our data show some clues that cytoskeletal reorganization may play roles in AD pathology. The early downregulation of miR-409-5p in AD progression might be a self-protective reaction to alleviate the synaptic damage induced by Aβ, which may be used as a potential early biomarker of AD.

Increased Gain in the Auditory Pathway, Alzheimer's Disease Continuum, and Air Pollution: Peripheral and Central Auditory System Dysfunction Evolves Across Pediatric and Adult Urbanites.

A major impediment in early diagnosis of Alzheimer's disease (AD) is the lack of robust non-invasive biomarkers of early brain dysfunction. Metropolitan Mexico City (MMC) children and young adults show hyperphosphorylated tau, amyloid-β, and α-synuclein within auditory and vestibular nuclei and marked dysmorphology in the ventral cochlear nucleus and superior olivary complex. Based on early involvement of auditory brainstem centers, we believe brainstem auditory evoked potentials can provide early AD biomarkers in MMC young residents. We measured brainstem auditory evoked potentials in MMC clinically healthy children (8.52±3.3 years) and adults (21.08±3.0 years, 42.48±8.5 years, and 71.2±6.4 years) compared to clean air controls (6.5±0.7 years) and used multivariate analysis adjusting for age, gender, and residency. MMC children had decreased latency to wave I, delays in waves III and V, and longer latencies for interwave intervals, consistent with delayed central conduction time of brainstem neural transmission. In sharp contrast, young adults have significantly shortened interwave intervals I-III and I-V. By the 5th decade, wave V and interval I-V were significantly shorter, while the elderly cohort had significant delay in mean latencies and interwave intervals. Compensatory plasticity, increased auditory gain, cochlear synaptopathy, neuroinflammation, and AD continuum likely play a role in the evolving distinct auditory pathology in megacity urbanites. Understanding auditory central and peripheral dysfunction in the AD continuum evolving and progressing in pediatric and young adult populations may shed light on the complex mechanisms of AD development and help identify strong noninvasive biomarkers. AD evolving from childhood in air pollution environments ought to be preventable.

APP processing and metabolism in corneal fibroblasts and epithelium as a potential biomarker for Alzheimer's disease

Alzheimer's disease (AD) primarily affects the brain and is the most common form of dementia worldwide. Despite more than a century of research, there are still no early biomarkers for AD. It has been reported that AD affects the eye, which is more accessible for imaging than the brain; however, links with the cornea have not been evaluated. To investigate whether the cornea could be used to identify possible diagnostic indicators of AD, we analyzed the proteolytic processing and isoforms of amyloid precursor protein (APP) and evaluated the expression of AD-related genes and proteins in corneal fibroblasts from wild-type (WT) corneas and corneas from patients with granular corneal dystrophy type 2 (GCD2), which is related to amyloid formation in the cornea. Reverse transcription polymerase chain reaction (RT-PCR) analysis was used to assess the expression of AD-related genes, i.e., APP, ADAM10, BACE1, BACE2, PSEN1, NCSTN, IDE, and NEP. RT-PCR and DNA sequencing analysis demonstrated that isoforms of APP770 and APP751, but not APP695, were expressed in corneal fibroblasts. Moreover, the mRNA ratio of APP770/APP751 isoforms was approximately 4:1. Western blot analysis also demonstrated the expression of a disintegrin and metalloprotease domain-containing protein 10 (ADAM10), beta-site APP-cleaving enzyme 1 (BACE1), nicastrin, insulin degradation enzyme, and neprilysin in corneal fibroblasts. Among these targets, the levels of immature ADAM10 and BACE1 protein were significantly increased in GCD2 cells. The expression levels of APP, ADAM10, BACE1, and transforming growth factor-beta-induced protein (TGFBIp) were also detected by western blot in human corneal epithelium. We also investigated the effects of inhibition of the autophagy-lysosomal and ubiquitin-proteasomal proteolytic systems (UPS) on APP processing and metabolism. These pathway inhibitors accumulated APP, α-carboxy-terminal fragments (CTFs), β-CTFs, and the C-terminal APP intracellular domain (AICD) in corneal fibroblasts. Analysis of microRNAs (miRNAs) revealed that miR-9 and miR-181a negatively coregulated BACE1 and TGFBIp, which was directly associated with the pathogenesis of AD and GCD2, respectively. Immunohistochemical analysis indicated that APP and BACE1 were distributed in corneal stroma cells, epithelial cells, and the retinal layer in mice. Collectively, we propose that the cornea, which is the transparent outermost layer of the eye and thus offers easy accessibility, could be used as a potential biomarker for AD diagnosis and progression.

Age‑ and brain region‑associated alterations of cerebral blood flow in early Alzheimer's disease assessed in AβPPSWE/PS1ΔE9 transgenic mice using arterial spin labeling.

It has been suggested that cerebral blood flow (CBF) alterations may be involved in the pathogenesis of Alzheimer's disease (AD). However, how CBF changes with age has not been detailed in AD, particularly in its early stages. The objective of the present study was to evaluate CBF in four brain regions (the hippocampus, entorhinal cortex, frontoparietal cortex and thalamus) of mice in four age groups, to mimic the respective stages of AD in humans [2 months (pre-clinical), 3.5 months (sub-clinical), 5 months (early-clinical) and 8 months (mid-clinical)], to understand the age-associated changes in selected brain regions and to elucidate the underlying vascular mechanisms. CBF was measured using magnetic resonance imaging-arterial spin labelling (ASL) under identical conditions across the age groups of AβPPSWE/PS1ΔE9 (APP/PS1) transgenic mice with AD. The results indicated age- and brain region-associated changes in CBF were associated with early AD. More precisely, an age-dependent increase in CBF (in the pre- and sub-clinical AD groups) was observed in the frontoparietal cortex and thalamus. Conversely, increased CBF demonstrated an age-dependent decline (in the early- and mid-clinical AD groups) in all examined brain regions. Among the regions, the thalamus had the greatest increase in CBF in the 2 and 3.5 months age groups, which was substantially different compared with the age-matched controls. An extension of vessel area was also noted to be age- and brain region-dependent. In particular, correlation analysis revealed significant associations of CBF with vessel area in the frontoparietal cortex and thalamus of APP/PS1 mice at ages 2 and 3.5 months, indicating that CBF increase may arise from vessel extension. The results of the present study suggested that ASL can detect age- and brain region-associated changes in CBF in mice with AD, and that ASL-measured CBF increase may be a potential diagnostic biomarker for early AD. The observation that CBF increase resulted from vessel extension may aid in the understanding of the vascular role in age-associated development of AD pathology, and provide preclinical evidence for AD patient management.

A fingerprint of amyloid plaques in a bitransgenic animal model of Alzheimer's disease obtained by statistical unmixing analysis of hyperspectral Raman data.

The global prevalence of Alzheimer's disease (AD) points to endemic levels, especially considering the increase of average life expectancy worldwide. AD diagnosis based on early biomarkers and better knowledge of related pathophysiology are both crucial in the search for medical interventions that are able to modify AD progression. In this study we used unsupervised spectral unmixing statistical techniques to identify the vibrational spectral signature of amyloid β aggregation in neural tissues, as early biomarkers of AD in an animal model. We analyzed spectral images composed of a total of 55 051 Raman spectra obtained from the frontal cortex and hippocampus of five bitransgenic APPswePS1ΔE9 mice, and colocalized amyloid β plaques by other fluorescence techniques. The Raman signatures provided a multifrequency fingerprint consistent with the results of synthesized amyloid β fibrils. The fingerprint obtained from unmixed analysis in neural tissues is shown to provide a detailed image of amyloid plaques in the brain, with the potential to be used as biomarkers for non-invasive early diagnosis and pathophysiology studies in AD on the retina.