Markers Of Alzheimer's Disease Research Articles

Accelerated Brain Aging in Amnestic Mild Cognitive Impairment: Relationships with Individual Cognitive Decline, Risk Factors for Alzheimer Disease, and Clinical Progression.

To determine whether a brain age prediction model could quantify individual deviations from a healthy brain-aging trajectory (predicted age difference [PAD]) in patients with amnestic mild cognitive impairment (aMCI) and to determine if PAD was associated with individual cognitive impairment. In this retrospective study, a machine learning approach was trained to determine brain age based on T1-weighted MRI scans. Two datasets were used for model training and testing-the Beijing Aging Brain Rejuvenation Initiative (BABRI) (616 healthy controls and 80 patients with aMCI, 2010-2018) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (589 healthy controls and 144 patients with aMCI, 2010-2018). A total of 974 healthy controls were used for model training (490 from BABRI and 484 from ADNI; age range, 49-95 years). The trained model was then tested on both healthy controls (126 from BABRI and 105 from ADNI) and patients with aMCI (80 from BABRI and 144 from ADNI) to estimate PAD (predicted age - actual age). Furthermore, the associations between PAD with cognitive impairment, genetic risk factors and pathologic markers of Alzheimer disease (AD), and clinical progression in patients with aMCI were examined using a partial correlation analysis, a two-way analysis of covariance, and a general linear model, respectively. Based on the prediction model, patients with aMCI were found to have higher PADs than those of healthy controls (BABRI: 2.65 ± 4.91 [standard deviation] vs 0.18 ± 4.79 [P < .001]; ADNI: 1.68 ± 5.28 vs 0.05 ± 4.41 [P < .001]). Moreover, the PAD was significantly associated with individual cognitive impairment in several cognitive domains in patients with aMCI (P < .05, corrected). When considering different AD-related risk factors, apolipoprotein E ε4 allele carriers were observed to have higher PADs than noncarriers (3.76 ± 4.82 vs 0.10 ± 5.05; P = .017), and patients with amyloid-positive aMCI were observed to have higher PADs than patients with amyloid-negative status (2.40 ± 5.25 vs 0.93 ± 5.20; P = .003). Finally, PAD combined with other markers of AD at baseline for differentiating between progressive and stable aMCI resulted in an area under the curve value of 0.87. The PAD is a sensitive imaging marker related to individual cognitive differences in patients with aMCI.Keywords: MR Imaging, Brain/Brain Stem, Brain Age, Machine Learning, Mild Cognitive Impairment, Structural MRI Supplemental material is available for this article. © RSNA, 2021.

Effects of Low-Intensity Transcranial Pulsed Ultrasound Treatment in a Model of Alzheimer's Disease

Alzheimer's disease (AD) is the most common neurodegenerative disease. One of the main pathology markers of AD is the beta-amyloid plaques (βA1–42) created from residues of the badly processed amyloid precursor protein. The accumulation of these plaques can induce neuroinflammation and oxidative stress and impair antioxidant mechanisms, culminating in cognitive and memory deficits. New therapies are necessary to treat AD as the approved drugs do not treat the progress of the disease. Transcranial low-intensity pulsed ultrasound (LIPUS) affects brain metabolism and could be tested as a treatment for AD. This study was aimed at evaluating the LIPUS treatment in a model of AD induced by βA1–42 intracerebroventricularly (ICV) and its effects on learning memory, neurotrophins, neuroinflammation and oxidative status. βA1–42 was administered ICV 24 h before the start of a 5-wk LIPUS treatment. The treatment with LIPUS improved recognition memory, as well as increasing nerve growth factor β and brain-derived neurotrophic factor levels in the hippocampus and cortex. There was a decrease in protein damage in the hippocampus treated with LIPUS. Neuroinflammation and oxidative stress were not present in the AD model used. The results indicated that LIPUS is a novel and promising adjuvant strategy for treatment of the late stage of AD.

Comparison of the decreases in regional cerebral blood flow in the posterior cingulate cortex, precuneus, and parietal lobe between suspected non-Alzheimer's disease pathophysiology and Alzheimer's disease.

Suspected non-Alzheimer's disease pathophysiology (SNAP) shows Alzheimer's disease (AD)-like neurodegeneration; however, amyloid β, which is a biological marker in AD, remains within normal levels. Since the effectiveness of anti-dementia drugs for AD on SNAP is unknown, it is important to distinguish between patients with SNAP and AD. We aimed to compare decreases in regional cerebral blood flow (rCBF) of the posterior cingulate cortex (PCC), precuneus, and parietal lobe critical to AD between SNAP and AD groups using the easy Z-score imaging system in single-photon emission computed tomography (eZIS-SPECT). We retrospectively analysed eZIS-SPECT data of 13 SNAP and 24 AD patients. The three indicators (severity, extent, and ratio) that distinguished AD patients from healthy controls in previous studies were automatically calculated and were compared between the SNAP and AD groups. Receiver operating characteristic curve analysis and the area under the curve (AUC) were used to evaluate the diagnostic performance of the three indicators of eZIS in discriminating between the two groups. The mean values of severity, extent, and ratio were significantly lower in the SNAP group than in the AD group (P=0.024, P=0.044, and P=0.045, respectively). The AUC values for severity, extent, and ratio were 0.668, 0.683, and 0.692, respectively. The present study suggests that SNAP shows milder reduction of rCBF in the PCC, precuneus, and parietal lobe as compared to AD. However, it may be difficult to distinguish between SNAP and AD with the degrees of decrease in rCBF in these regions.

Blood-Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease.

Objective:Blood–brain barrier (BBB) breakdown has been suggested to be an early biomarker in human cognitive impairment. However, the relationship between BBB breakdown and brain pathology, most commonly Alzheimer disease (AD) and vascular disease, is still poorly understood. The present study measured human BBB function in mild cognitive impairment (MCI) patients on 2 molecular scales, specifically BBB’s permeability to water and albumin molecules.Methods:Fifty-five elderly participants were enrolled, including 33 MCI patients and 22 controls. BBB permeability to water was measured with a new magnetic resonance imaging technique, water extraction with phase contrast arterial spin tagging. BBB permeability to albumin was determined using cerebrospinal fluid (CSF)/serum albumin ratio. Cognitive performance was assessed by domain-specific composite scores. AD pathology (including CSF Aβ and ptau) and vascular risk factors were examined.Results:Compared to cognitively normal subjects, BBB in MCI patients manifested an increased permeability to small molecules such as water but was no more permeable to large molecules such as albumin. BBB permeability to water was found to be related to AD markers of CSF Aβ and ptau. On the other hand, BBB permeability to albumin was found to be related to vascular risk factors, especially hypercholesterolemia, but was not related to AD pathology. BBB permeability to small molecules, but not to large molecules, was found to be predictive of cognitive function.Interpretation:These findings provide early evidence that BBB breakdown is related to both AD and vascular risks, but their effects can be differentiated by spatial scales. BBB permeability to small molecules has a greater impact on cognitive performance.

Sentence comprehension in ageing and Alzheimer's disease

AbstractThe ability to correctly interpret complex syntax and long sentences is gradually impaired as people age. Typical ageing is characterised by working memory deficits, which are thought to play an important role in determining whether syntax can be comprehended correctly, and neurodegenerative conditions such as Alzheimer's disease (AD) are thought to exacerbate these limitations. Furthermore, declines in processing speed appear to cause increasing difficulty in the proper allocation of cognitive resources necessary for sentence processing. Typically ageing adults may compensate for these deficits successfully when interpreting sentences using semantics or intact cognitive functions, but AD patients may exhibit deficits too severe for this to occur. The causes of syntax comprehension deficits in Alzheimer's are still contested, and may consist of language‐specific impairments or deficits in general cognition impacting linguistic behaviour. In this review, we aim to give an overview of the main markers of cognitive ageing and AD in the domain of sentence comprehension, as well as discuss potential underlying factors that may affect sentence comprehension in older speakers and Alzheimer's patients.

The clinical correlation of proinflammatory and anti-inflammatory biomarkers with Alzheimer disease: a meta-analysis.

Numerous studies have indicated the role of inflammation in the pathogenesis of Alzheimer's disease (AD). However, the exact role of inflammatory markers in AD is still unclear. The main objective of the current study was to find out the association between the level of inflammatory markers and AD. The relevant articles have been extracted from PubMed as per the inclusion and exclusion criteria of the study. The mean value with standard deviation and number of participants in AD and control groups were extracted from relevant articles. The inverse variance was used as a statistical method and standard mean difference (SMD) as effect measure with 95% C.I. The random effect model was used and all analyses were done using Rev. Man 5.0. A total of 38 articles have been found relevant and selected for analysis. The overall estimate results have shown that the level of IL-6, TGF-β1, and IL-1α were increased significantly in AD patients as compared to the control group among all other pro-inflammatory, inflammatory and anti-inflammatory mediators. The findings of the current study suggest that IL-6, TGF-β1, and IL-1α may be a useful early marker in AD. However, further studies are required to confirm the exact utility of these inflammatory markers.

Comparative Analysis of Multiple Neurodegenerative Diseases Based on Advanced Epigenetic Aging Brain.

Background: Neurodegenerative Diseases (NDs) are age-dependent and include Alzheimer’s disease (AD), Parkinson’s disease (PD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and so on. There have been numerous studies showing that accelerated aging is closely related (even the driver of) ND, thus promoting imbalances in cellular homeostasis. However, the mechanisms of how different ND types are related/triggered by advanced aging are still unclear. Therefore, there is an urgent need to explore the potential markers/mechanisms of different ND types based on aging acceleration at a system level.Methods: AD, PD, PSP, FTD, and aging markers were identified by supervised machine learning methods. The aging acceleration differential networks were constructed based on the aging score. Both the enrichment analysis and sensitivity analysis were carried out to investigate both common and specific mechanisms among different ND types in the context of aging acceleration.Results: The extracellular fluid, cellular metabolisms, and inflammatory response were identified as the common driving factors of cellular homeostasis imbalances during the accelerated aging process. In addition, Ca ion imbalance, abnormal protein depositions, DNA damage, and cytoplasmic DNA in macrophages were also revealed to be special mechanisms that further promote AD, PD, PSP, and FTD, respectively.Conclusion: The accelerated epigenetic aging mechanisms of different ND types were integrated and compared through our computational pipeline.

Risks and Prognoses of Alzheimer's Disease and Vascular Dementia in Patients With Insomnia: A Nationwide Population-Based Study.

This study aimed to investigate the risk and prognosis of Alzheimer's disease (AD) and vascular dementia (VaD) in patients with insomnia using the National Health Insurance Service database covering the entire population of the Republic of Korea from 2007 to 2014. In total, 2,796,871 patients aged 40 years or older with insomnia were enrolled, and 5,593,742 controls were matched using a Greedy digit match algorithm. Mortality and the rate of admission to a long-term care facility were estimated using multivariable Cox analysis. Of all patients with insomnia, 138,270 (4.94%) and 26,706 (0.96%) were newly diagnosed with AD and VaD, respectively. The incidence rate ratios for AD and VaD were 1.73 and 2.10, respectively, in patients with insomnia compared with those without. Higher mortality rates and long-term care facility admission rates were also observed in patients with dementia in the insomnia group. Known cardiovascular risk factors showed interactions with the effects of insomnia on the risk of AD and VaD. However, the effects of insomnia on the incidence of AD and VaD were consistent between the groups with and without cardiovascular risk factors. Insomnia is a medically modifiable and policy-accessible risk factor and prognostic marker of AD and VaD.

245 Sleep and cortical thickness are influenced by surgical menopause

Abstract Introduction Early loss of 17β-estradiol (E2), as experienced by women with bilateral salpingo-oophorectomy (BSO; removal of ovaries and fallopian tubes), is associated with increased prevalence of sleep disorders and greater Alzheimer’s disease (AD) risk. In older adults, poor sleep heightens AD risk; hypoxia increases markers for incipient AD, including circulating Aβ, and is linked to prefrontal cortical thinning. Thus, we wondered: 1) if this at-risk population of middle-aged women with BSO had sleep hypoxia, measured by oxygen desaturation, and 2) whether this related to decreased prefrontal cortical thickness in women taking and not taking estradiol therapy (ET). Methods Sleep and percent oxygen desaturation (SPO2%) were measured via at-home polysomnography (TEMEC). Prefrontal cortical thickness was obtained from T1-weighted structural scans using the CIVET pipeline. We recruited middle-age women with BSO, some of whom were taking ET (BSO+ET; n=15), and some not (BSO; n=15). We compared their sleep and cortical thickness with that of age and education-matched premenopausal controls (AMC; n=18). Results Women with BSO (BSO, BSO+ET) had lower minimum SPO2% values than AMC, and thinner right medial orbitofrontal (rmOF) cortices. There was a trend for women with BSO to have lower average SPO2% than AMC. Analyses separating groups based on ET therapy status (BSO vs BSO+ET vs AMC) revealed only trending differences between groups, such that women with BSO tended to have lower minimum SPO2% and thinner rmOF cortices than AMC. Conclusion These preliminary results suggest early loss of E2 due to BSO may drive greater drops in SPO2% in middle-age women, and may be related to reduced prefrontal cortical thickness. This study is the first to show hypoxia in women with BSO. Support (if any) Ontario Graduate Scholarship Award (to LG), Alzheimer’s Association Research Fellowship (co-sponsored by Brain Canada Foundation; AARF-17-504715 to NJG), Alzheimer’s Society Canada Postdoctoral Fellowship (to AA), Canadian Institutes of Health Research (CIHR) Masters Award (to LG, AB, and RR), Wilfred and Joyce Posluns Chair in Women’s Brain Health and Aging (from the Posluns Family Foundation, CIHR, Ontario Brain Institute, and Alzheimer Society of Canada; WJP-150643 to GE)

Traumatic Brain Injury Exacerbates Alzheimer's Disease Pathology in the Retina of Rats

Alzheimer's disease (AD) is a neurodegenerative condition that affects 5.7 million people in the U.S. alone, representing the leading form of dementia. Additionally, traumatic brain injury (TBI), which can arise from sport concussions, military combat and other causes, is associated with a 2.3-fold higher risk of developing AD and AD-related dementias. Moreover, AD can also lead to visual impairment, and recent studies have found that AD histopathology manifests in the retina, which is an extension of the central nervous system. However, the pathophysiological link between TBI and AD remains poorly understood. In this study we set out to evaluate the effects of TBI, AD, and their combination, on retinal histopathology. Several animal models have been developed to investigate the mechanisms of AD but have been limited by imperfect recapitulation of human pathology. Here we take advantage of a transgenic rat model (Tg-F344) that more faithfully mimics human AD pathology, and subject it to a TBI paradigm. Wild-type and transgenic rats were randomly selected to undergo a unilateral controlled cortical impact (CCI). At 15 months of age, the rats were sacrificed and the eyes subsequently removed, fixed, and processed. Retinas were sectioned and analyzed using immunofluorescent and standard histological staining techniques. Our results confirm the presence of AD markers in transgenic retinas, and an increased severity of AD pathology due to TBI. This has meaningful implications in understanding the pathophysiology of AD in relation to TBI within the retina, which could lead to better treatments and to the development of retinal biomarkers for improved AD diagnosis.

Dysbiosis and Alzheimer's Disease: A Role for Chronic Stress?

Alzheimer’s disease (AD) is an incurable, neuropsychiatric, pathological condition that deteriorates the worth of geriatric lives. AD is characterized by aggregated senile amyloid plaques, neurofibrillary tangles, neuronal loss, gliosis, oxidative stress, neurotransmitter dysfunction, and bioenergetic deficits. The changes in GIT composition and harmony have been recognized as a decisive and interesting player in neuronal pathologies including AD. Microbiota control and influence the oxidoreductase status, inflammation, immune system, and the endocrine system through which it may have an impact on the cognitive domain. The altered and malfunctioned state of microbiota is associated with minor infections to complicated illnesses that include psychosis and neurodegeneration, and several studies show that microbiota regulates neuronal plasticity and neuronal development. The altered state of microbiota (dysbiosis) may affect behavior, stress response, and cognitive functions. Chronic stress-mediated pathological progression also has a well-defined role that intermingles at various physiological levels and directly impacts the pathological advancement of AD. Chronic stress-modulated alterations affect the well-established pathological markers of AD but also affect the gut–brain axis through the mediation of various downstream signaling mechanisms that modulate the microbial commensals of GIT. The extensive literature reports that chronic stressors affect the composition, metabolic activities, and physiological role of microbiota in various capacities. The present manuscript aims to elucidate mechanistic pathways through which stress induces dysbiosis, which in turn escalates the neuropathological cascade of AD. The stress–dysbiosis axis appears a feasible zone of work in the direction of treatment of AD.

Drotaverine Inhibitor of PDE4: Reverses the Streptozotocin Induced Alzheimer's Disease in Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with decline in memory and cognitive impairments. Phosphodiesterase IV (PDE4) protein, an intracellular cAMP levels regulator, when inhibited act as potent neuroprotective agents by virtue of ceasing the activity of Pro-inflammatory mediators. The complexity of AD etiology has ever since compelled the researchers to discover multifunctional compounds to combat the AD and neurodegeneration. The aim of this study was to probe into role of drotaverine a PDE4 inhibitor in the management of AD. Albino mice were divided into seven groups (n = 10). Group 1 control group received carboxy methyl cellulose (CMC 1mL/kg), group II diseased group treated with streptozotocin (STZ 3mg/kg) by intracerebroventricular (ICV) route, group III administered standard drug Piracetam 200mg/kg and groups IV-VII were given drotaverine (10, 20, 40, and 80mg/kg i/p respectively). Groups II-VII were given STZ (3mg/kg, ICV) on 1st and 3rd day of treatment to induce AD. All the groups were given their respective treatments for 23days. Improvement in learning and memory was evaluated by using behavioral tests like open field test, elevated plus maze test, Morris water maze test and passive avoidance test. Furthermore, brain levels of biochemical markers of oxidative stress, neurotransmitters, β-amyloid and tau protein were also measured. Drotaverine showed statistically significant dose dependent improvement in behavioral and biochemical markers of AD: the maximum response was achieved at a dose level of 80mg/kg. The Study concluded that drotaverine ameliorates cognitive impairment and as well as exhibited modulated the brain levels of neurotransmitters.

Ocular Health of Octodon degus as a Clinical Marker for Age-Related and Age-Independent Neurodegeneration

The aging process and age-related diseases such as Alzheimer’s disease (AD), are very heterogeneous and multifactorial, making it challenging to diagnose the disease based solely on genetic, behavioral tests, or clinical history. It is yet to be explained what ophthalmological tests relate specifically to aging and AD. To this end, we have selected the common degu (Octodon degus) as a model for aging which develops AD-like signs to conduct ophthalmological screening methods that could be clinical markers of aging and AD. We investigated ocular health using ophthalmoscopy, fundus photography, intraocular pressure (IOP), and pupillary light reflex (PLR). The results showed significant presence of cataracts in adult degus and IOP was also found to increase significantly with advancing age. Age had a significant effect on the maximum pupil constriction but other pupil parameters changed in an age-independent manner (PIPR retention index, resting pupil size, constriction velocity, redilation plateau). We concluded that degus have underlying factors at play that regulate PLR and may be connected to sympathetic, parasympathetic, and melanopsin retinal ganglion cell (ipRGC) deterioration. This study provides the basis for the use of ocular tests as screening methods for the aging process and monitoring of neurodegeneration in non-invasive ways.

Functional genomics study of protein inhibitor of activated STAT1 in mouse hippocampal neuronal cells revealed by RNA sequencing.

Protein inhibitor of activated STAT1 (PIAS1), a small ubiquitin-like modifier (SUMO) E3 ligase, was considered to be an inhibitor of STAT1 by inhibiting the DNA-binding activity of STAT1 and blocking STAT1-mediated gene transcription in response to cytokine stimulation. PIAS1 has been determined to be involved in modulating several biological processes such as cell proliferation, DNA damage responses, and inflammatory responses, both in vivo and in vitro. However, the role played by PIAS1 in regulating neurodegenerative diseases, including Alzheimer’s disease (AD), has not been determined. In our study, significantly different expression levels of PIAS1 between normal controls and AD patients were detected in four regions of the human brain. Based on a functional analysis of Pias1 in undifferentiated mouse hippocampal neuronal HT-22 cells, we observed that the expression levels of several AD marker genes could be inhibited by Pias1 overexpression. Moreover, the proliferation ability of HT-22 cells could be promoted by the overexpression of Pias1. Furthermore, we performed RNA sequencing (RNA-seq) to evaluate and quantify the gene expression profiles in response to Pias1 overexpression in HT-22 cells. As a result, 285 significantly dysregulated genes, including 79 upregulated genes and 206 downregulated genes, were identified by the comparison of Pias1/+ cells with WT cells. Among these genes, five overlapping genes, including early growth response 1 (Egr1), early growth response 2 (Egr2), early growth response 3 (Egr3), FBJ osteosarcoma oncogene (Fos) and fos-like antigen 1 (Fosl1), were identified by comparison of the transcription factor binding site (TFBS) prediction results for STAT1, whose expression was evaluated by qPCR. Three cell cycle inhibitors, p53, p18 and p21, were significantly downregulated with the overexpression of Pias1. Analysis of functional enrichment and expression levels showed that basic region leucine zipper domain-containing transcription factors including zinc finger C2H2 (zf-C2H2), homeobox and basic/helix-loop-helix (bHLH) in several signaling pathways were significantly involved in PIAS1 regulation in HT-22 cells. A reconstructed regulatory network under PIAS1 overexpression demonstrated that there were 43 related proteins, notably Nr3c2, that directly interacted with PIAS1.

Berberine ameliorates neuronal AD‐like change via activating Pi3k/PGCε pathway

IR (insulin resistance) in diabetic brain gave rise to the generation of toxic factor Aβ42 and axon collapse which were the marker of AD (Alzheimer's disease)-like lesions in the circumstance of diabetes mellitus. But the underling molecular mechanism was not clear. Chronic HGHI (high glucose and high insulin) exposure accelerates IR has been reported in type II diabetes models. Berberine has been shown to promising effect for IR in vitro and in vivo. This study demonstrates the protective effect and the underlying mechanism of berberine on HGHI-induced IR. HGHI-induced cells were used to mimic the hyperinsulinemia resulting in IR. Berberine was used to uncover the mechanisms for the treatment of hyperinsulinemia in IR model. Morris water maze (MWM), PET imaging, CCK8 assay, ELISA assay, glucose kits, microscopy, and western blot analysis were performed to evaluate the protective effects of berberine. Berberine-improved HGHI-induced IR was correlated with the increase of glucose application in neurons. Meanwhile, the expressions of Pi3K, as well as GLUT3, PKCε, and APP were downregulated in the model, while p-IRS Ser307 was upregulated compared with Normal group. Fortunately, these scenes were reversed by berberine administration. Furthermore, berberine decreased GSK3β Y216 expressions, inhibited the production of oligomer Aβ42 and extended neuronal axon. The monomeric berberine treatment improves IR that may be involved in glucose effective application, rectifying the related proteins of the aberrant insulin pathway. Additionally, it suppressed the generation of Aβ42 and ameliorated neuron axon damage. Finally, berberine improves DM (diabetes mellitus)-induced cognitive impairment.

Specific detection of Staphylococcus aureus infection and marker for Alzheimer disease by surface enhanced Raman spectroscopy using silver and gold nanoparticle-coated magnetic polystyrene beads

Targeted and effective therapy of diseases demands utilization of rapid methods of identification of the given markers. Surface enhanced Raman spectroscopy (SERS) in conjunction with streptavidin–biotin complex is a promising alternative to culture or PCR based methods used for such purposes. Many biotinylated antibodies are available on the market and so this system offers a powerful tool for many analytical applications. Here, we present a very fast and easy-to-use procedure for preparation of streptavidin coated magnetic polystyrene–Au (or Ag) nanocomposite particles as efficient substrate for surface SERS purposes. As a precursor for the preparation of SERS active and magnetically separable composite, commercially available streptavidin coated polystyrene (PS) microparticles with a magnetic core were utilized. These composites of PS particles with silver or gold nanoparticles were prepared by reducing Au(III) or Ag(I) ions using ascorbic acid or dopamine. The choice of the reducing agent influences the morphology and the size of the prepared Ag or Au particles (15–100 nm). The prepare composites were also characterized by HR-TEM images, mapping of elements and also magnetization measurements. The content of Au and Ag was determined by AAS analysis. The synthesized composites have a significantly lower density against magnetic composites based on iron oxides, which considerably decreases the tendency to sedimentation. The polystyrene shell on a magnetic iron oxide core also pronouncedly reduces the inclination to particle aggregation. Moreover, the preparation and purification of this SERS substrate takes only a few minutes. The PS composite with thorny Au particles with the size of approximately 100 nm prepared was utilized for specific and selective detection of Staphylococcus aureus infection in joint knee fluid (PJI) and tau protein (marker for Alzheimer disease).

Abstract P61: Pulsatility Index Outperforms Conventional Imaging Markers in the Association With Cognition in Community Subjects

Increase in pulsatility index (PI), measured by the transcranial Doppler (TCD), correlates with cognitive impairment and is associated with progression of non-demented patients into Alzheimer’s disease (AD) with dementia, suggesting that increase in small vessel resistance is a critical marker of cognitive decline. No study compared PI and MRI markers for small vessel disease or AD that have been shown to be associated with worse cognitive functions. The objectives of this study include: (i) compare PI against conventional MRI markers in its association with cognition, and (ii) investigate the association of PI and cognition in the presence of vascular risk factors. We measured clinical data and PI in the middle cerebral artery in 331 stroke- and dementia-free community subjects. General cognition was assessed using Hong Kong-Montreal Cognitive Assessment. Conventional imaging markers (including lacunes, white matter hyperintensities (WMH), brain parenchymal fraction (BPF), cerebral microbleeds, Alzheimer’s Disease Resemblance Atrophy Index (ADRAI)) were assessed by MRI. Linear regression models were used to compare the sensitivity of PI against conventional MRI markers (including WMH, BPF, ADRAI, lacune and cerebral microbleeds count), with age and years of education entered as covariates. PI was negatively associated with cognition (standardised b=-0.122, p=0.01). PI outperformed (standardised b=-0.118, p=0.012) other imaging markers and contributes to 1.1% change in the variance. PI was associated with higher systolic blood pressure (standardised b=0.122, p=0.028), and level of triglyceride (standardised b = 0.126, p = 0.021). To conclude, PI is associated with cognition, higher levels of blood pressure and triglycerides, suggesting a vascular component in cognitive decline. PI outperforms conventional MRI markers in the association with cognition in community subjects without dementia. As TCD is non-invasive, portable with a lower cost than MRI, PI may serve as a simple marker in monitoring cerebral small vessel resistance and cognition in older people.

High-Throughput Metabolomics for Discovering Potential Biomarkers and Identifying Metabolic Mechanisms in Aging and Alzheimer's Disease.

Alzheimer’s disease (AD) is an aging-related neurodegenerative disease. We aimed to investigate the metabolic mechanisms of aging and AD and to identify potential biomarkers for the early screening of AD in a natural aging population. To analyze the plasma metabolites related to aging, we conducted an untargeted metabolomics analysis using ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry in a two-stage cross-sectional study. Spearman’s correlation analysis and random forest were applied to model the relationship between age and each metabolite. Moreover, a systematic review of metabolomics studies of AD in the PubMed, Cochrane and Embase databases were searched to extract the differential metabolites and altered pathways from original studies. Pathway enrichment analysis was conducted using Mummichog. In total, 669 metabolites were significantly altered with aging, and 12 pathways were enriched and correlated with aging. Three pathways (purine metabolism, arginine and proline metabolism, and the TCA cycle) were shared between aging and AD. Arginine and proline metabolism play a key role in the progression from healthy to mild cognitive impairment and to AD in the natural aging population. Three metabolites, 16-a-hydroxypregnenolone, stearic acid and PC[16:0/22:5(4Z,7Z,10Z,13Z,16Z)] were finally proposed as potential markers of AD in the natural aging population. The underlying mechanism shared between aging and AD and the potential biomarkers for AD diagnosis were proposed based on multistep comparative analysis.

Spouse-Appraised Memory Functioning Predicts Memory Decline Better Than Subjective Memory Complaints in Community Dwelling Older Adults at Genetic Risk for Alzheimer's Disease.

Objective: Alzheimer's disease (AD) begins with subtle memory decline, years before dementia onset. The presence of subjective memory complaints (SMC) has been proposed as a marker of preclinical AD. However, recent evidence has demonstrated early and progressive loss of awareness of memory difficulties in non-demented older adults harboring AD pathology. We investigated the respective contributions of SMC and spouse-appraised memory functioning (SAM) to predict memory decline in a large cohort of community dwelling older adults.Methods: The Wisconsin Longitudinal Study collected cognitive data from a community-based cohort of 3,583 participants in both 2005 and 2011. The participant and the participant's spouse were each asked to rate the participant's memory functioning using a Likert scale. We predicted change in objective episodic memory with models including baseline SMC, baseline SAM, or both SMC and SAM. We also evaluated an awareness index (SMC minus SAM). We then tested the interaction between Apolipoprotein E (APOE ε4) carrier status and SMC/SAM to evaluate whether the effects were driven by individuals at-risk for AD pathology.Results: In separate models, SMC (−0.081 ± 0.036, p = 0.025) and SAM (−0.084 ± 0.278, p = 0.003) were both associated with memory decline over ~6 years. However, the AI was not significantly associated with memory decline (0.031 ± 0.024, p = 0.19). When both predictors were included in the same model, SAM (−0.074 ± 0.03, p = 0.0092) was associated with memory decline, while SMC was not significant (−0.061 ± 0.04, p = 0.99). The association between SAM and memory decline was stronger in the APOE ε4 carriers than in the non-carriers (APOE-by-SAM interaction: F = 6.07; p = 0.002), and follow up analyses revealed that SAM was particularly predictive of decline only for APOE ε4 carriers. The association between SMC and memory decline was independent of APOE ε4 carrier status (APOE-by-SMC interaction: F = 2.29; p = 0.13).Conclusions: Spouse-appraised memory functioning was more predictive of memory decline than SMC or an awareness index, particularly in APOE ε4 carriers, who are at increased risk for AD pathology.

Paucity of Entorhinal Cortex Pathology of the Alzheimer's Type in SuperAgers with Superior Memory Performance.

Advancing age is typically associated with declining memory capacity and increased risk of Alzheimer's disease (AD). Markers of AD such as amyloid plaques (AP) and neurofibrillary tangles (NFTs) are commonly found in the brains of cognitively average elderly but in more limited distribution than in those at the mild cognitive impairment and dementia stages of AD. Cognitive SuperAgers are individuals over age 80 who show superior memory capacity, at a level consistent with individuals 20-30years their junior. Using a stereological approach, the current study quantitated the presence of AD markers in the memory-associated entorhinal cortex (ERC) of seven SuperAgers compared with six age-matched cognitively average normal control individuals. Amyloid plaques and NFTs were visualized using Thioflavin-S histofluorescence, 6E10, and PHF-1 immunohistochemistry. Unbiased stereological analysis revealed significantly more NFTs in ERC in cognitively average normal controls compared with SuperAgers (P < 0.05) by a difference of ~3-fold. There were no significant differences in plaque density. To highlight relative magnitude, cases with typical amnestic dementia of AD showed nearly 100 times more entorhinal NFTs than SuperAgers. The results suggest that resistance to age-related neurofibrillary degeneration in the ERC may be one factor contributing to preserved memory in SuperAgers.