Markers Of Alzheimer's Disease Research Articles

The Role of Steroidomics in the Diagnosis of Alzheimer's Disease and Type 2 Diabetes Mellitus.

Epidemiological studies suggest an association between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). This study aimed to investigate the pathophysiological markers of AD vs. T2DM for each sex separately and propose models that would distinguish control, AD, T2DM, and AD-T2DM comorbidity groups. AD and T2DM differed in levels of some circulating steroids (measured mostly by GC-MS) and in other observed characteristics, such as markers of obesity, glucose metabolism, and liver function tests. Regarding steroid metabolism, AD patients (both sexes) had significantly higher sex hormone binding globulin (SHBG), cortisol, and 17-hydroxy progesterone, and lower estradiol and 5α-androstane-3α,17β-diol, compared to T2DM patients. However, compared to healthy controls, changes in the steroid spectrum (especially increases in levels of steroids from the C21 group, including their 5α/β-reduced forms, androstenedione, etc.) were similar in patients with AD and patients with T2DM, though more expressed in diabetics. It can be assumed that many of these steroids are involved in counter-regulatory protective mechanisms that mitigate the development and progression of AD and T2DM. In conclusion, our results demonstrated the ability to effectively differentiate AD, T2DM, and controls in both men and women, distinguish the two pathologies from each other, and differentiate patients with AD and T2DM comorbidities.

Study of the relationships between quantitative measurements of cerebral vascularization obtained by artificial intelligence, cognitive functions, and biomarkers of Alzheimer’s disease (P4-6.005)

<h3>Objective:</h3> Explore the relationship between the diameters and the volumes of the intracranial arteries and i) cognition; ii) Alzheimer’s Disease (AD) biomarkers, specifically hippocampal and cerebral atrophy and PET amyloid burden; iii) cognitive decline. <h3>Background:</h3> With the aging of the world population, approximately 78 million people worldwide will be affected by a major neurocognitive disorder (NCD) in 2030, with up to 80% of cases being of AD type. However, its etiology remains unclear. Given the growing evidence supporting a relationship between vascular factors and AD, we explored this hypothesis using a novel artificial intelligence (AI) algorithm. <h3>Design/Methods:</h3> Of the 409 participants (42–95 years old) selected from the OASIS-3 database, 338 had a normal cognition, 53, a questionable NCD, 16, a mild NCD, and 2, a major NCD. Intracranial arteries were evaluated by time-of-flight magnetic resonance angiography (TOF-MRA) and their measurements were calculated using a newly developed AI system. Cognitive status was assessed by MMSE, CDR, and several neuropsychological tests, including Logical Memory and Trail Making tests. Amyloid burden was visualized by amyloid PET with contrast (Pittsburgh Compound B or Florbetapir) and quantified using the Centiloid scale. Brain and hippocampal volumes were assessed by T1-weighted MRI and the resulting images were processed by the Freesurfer image analysis suite. <h3>Results:</h3> The anterior choroidal arteries (AchA) had the most associations (nonlinear and negative) with cognitive functions and AD markers. Conversely, the anterior cerebral (ACA), basilar, and 1^st segment of the posterior cerebral arteries (PCA-P1) had very little relationship with cognition. Among the statistically significant results, the correlations were of low magnitude. <h3>Conclusions:</h3> Using TOF-MRA imaging and AI, we were able to calculate the quantitative measurements of the intracranial arteries and thus assess their association with certain AD elements. Future research to further explore the vascular hypothesis of AD should be conducted in order to confirm these findings. <b>Disclosure:</b> Miss Ni has nothing to disclose. Dr. Janelle has nothing to disclose. Mr. Dumais has received personal compensation for serving as an employee of Imeka. Dr. Bocti has nothing to disclose. Kevin Whittingstall has nothing to disclose.

Cerebroprotein hydrolysate attenuates neurodegenerative changes in Alzheimer's mice model via ferroptosis pathway.

Introduction: Cerebroprotein hydrolysate has been proven to improve cognitive function in patients with Alzheimer's disease (AD). We explored the safety and effectiveness of the clinical administration of oral cerebroprotein hydrolysate in AD, and possible mechanisms related to the neuronal ferroptosis pathway. Methods: Three-month-old male APP/PS1 double-transgenic mice were randomly divided into AD model (n = 8) and intervention (n = 8) groups. Eight non-transgenic wild-type (WT) C57 mice were used as age-matched controls. The experiments were started at the age of 6 months. The intervention group was then administered cerebroprotein hydrolysate nutrient solution (11.9mg/kg/day) via chronic gavage, the other groups received an identical volume of distilled water. Behavioural experiments were performed after 90days of continuous administration. Serum and hippocampal tissues were then collected for histomorphological observation, tau and p-tau expression, and ferroptosis markers analysis. Results: Cerebroprotein hydrolysate simplified movement trajectories and shortened escape latencies of APP/PS1 mice in the Morris water maze test. Neuronal morphologies were restored in hippocampal tissues on haematoxylin-eosin staining. In the AD-model group, Aβ protein and p-tau/tau expression levels were elevated, plasma Fe2+ and malondialdehyde levels were elevated, GXP4 protein expression and plasma glutathione levels declined than controls. All indices improved after cerebroprotein hydrolysate intervention. Conclusion: Cerebroprotein hydrolysate improves learning and memory function, alleviates neuronal damage, and reduces the deposition of pathological AD markers in AD mice, which may be related to the inhibition of neuronal ferroptosis.

Biological brain age prediction using machine learning on structural neuroimaging data: Multi-cohort validation against biomarkers of Alzheimer's disease and neurodegeneration stratified by sex.

Brain-age can be inferred from structural neuroimaging and compared to chronological age (brain-age delta) as a marker of biological brain aging. Accelerated aging has been found in neurodegenerative disorders like Alzheimer's disease (AD), but its validation against markers of neurodegeneration and AD is lacking. Here, imaging-derived measures from the UK Biobank dataset (N=22,661) were used to predict brain-age in 2,314 cognitively unimpaired (CU) individuals at higher risk of AD and mild cognitive impaired (MCI) patients from four independent cohorts with available biomarker data: ALFA+, ADNI, EPAD, and OASIS. Brain-age delta was associated with abnormal amyloid-β, more advanced stages (AT) of AD pathology and APOE-ε4 status. Brain-age delta was positively associated with plasma neurofilament light, a marker of neurodegeneration, and sex differences in the brain effects of this marker were found. These results validate brain-age delta as a non-invasive marker of biological brain aging in non-demented individuals with abnormal levels of biomarkers of AD and axonal injury.

Evaluation of the effects of herpes simplex glycoprotein B on complement system and cytokines in in vitro models of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that causes memory loss and dementia and is characterized by a decline in cognitive functions. Brain infections, especially induced by herpes simplex virus type-1 (HSV-1), are suggested to play a key role in the pathogenesis of AD. Within the scope of this study, two different AD models (Tau model and amyloid beta [Aβ]) were created in the SH-SY5Y cell line, and HSV glycoprotein B (gB) was applied to the cell line and on the generated AD models. Study groups (n = 3) were designed as (1) control, (2) HSV-gB group, (3) retinoic acid (RA) and brain derived neurotrophic factor (BDNF) induced Alzheimer's model (AD), (4) RA and BDNF induced Alzheimer's model + HSV-gB (ADH), (5) Aβ 1-42 peptide-induced Alzheimer's model (Aβ), and (6) Aβ 1-42 peptide-induced Alzheimer's model + HSV-gB (AβH). Levels of complement proteins and cytokines were determined comparatively. In addition, specific markers of AD (hyperphosphorylated Tau proteins, Aβ 1-40 peptide and amyloid precursor protein) were measured in all groups. HSV-gB administration was found to increase Aβ and hyperphosphorylated Tau levels, similar to AD models. In addition, our data confirmed that the immune system and chronic inflammation might have a crucial role in AD development and that HSV-1 infection might also be an underlying factor of AD.

Reproducible Abnormalities and Diagnostic Generalizability of White Matter in Alzheimer's Disease.

Alzheimer's disease (AD) is associated with the impairment of white matter (WM) tracts. The current study aimed to verify the utility of WM as the neuroimaging marker of AD with multisite diffusion tensor imaging datasets [321 patients with AD, 265 patients with mild cognitive impairment (MCI), 279 normal controls (NC)], a unified pipeline, and independent site cross-validation. Automated fiber quantification was used to extract diffusion profiles along tracts. Random-effects meta-analyses showed a reproducible degeneration pattern in which fractional anisotropy significantly decreased in the AD and MCI groups compared with NC. Machine learning models using tract-based features showed good generalizability among independent site cross-validation. The diffusion metrics of the altered regions and the AD probability predicted by the models were highly correlated with cognitive ability in the AD and MCI groups. We highlighted the reproducibility and generalizability of the degeneration pattern of WM tracts in AD.

Can T1-Weighted Magnetic Resonance Imaging Significantly Improve Mini-Mental State Examination-Based Distinguishing Between Mild Cognitive Impairment and Early-Stage Alzheimer's Disease?

Detecting early-stage Alzheimer's disease (AD) is still problematic in clinical practice. This work aimed to find T1-weighted MRI-based markers for AD and mild cognitive impairment (MCI) to improve the screening process. Our assumption was to build a screening model that would be accessible and easy to use for physicians in their daily clinical routine. The multinomial logistic regression was used to detect status: AD, MCI, and normal control (NC) combined with the Bayesian information criterion for model selection. Several T1-weighted MRI-based radiomic features were considered explanatory variables in the prediction model. The best radiomic predictor was the relative brain volume. The proposed method confirmed its quality by achieving a balanced accuracy of 95.18%, AUC of 93.25%, NPV of 97.93%, and PPV of 90.48% for classifying AD versus NC for the European DTI Study on Dementia (EDSD). The comparison of the two models: with the MMSE score only as an independent variable and corrected for the relative brain value and age, shows that the addition of the T1-weighted MRI-based biomarker improves the quality of MCI detection (AUC: 67.04% versus 71.08%) while maintaining quality for AD (AUC: 93.35% versus 93.25%). Additionally, among MCI patients predicted as AD inconsistently with the original diagnosis, 60% from ADNI and 76.47% from EDSD were re-diagnosed as AD within a 48-month follow-up. It shows that our model can detect AD patients a few years earlier than a standard medical diagnosis. The created method is non-invasive, inexpensive, clinically accessible, and efficiently supports AD/MCI screening.

Elevated plasma p-tau181 levels unrelated to Alzheimer’s disease pathology in amyotrophic lateral sclerosis

BackgroundPhosphorylated-tau181 (p-tau181), a specific marker of Alzheimer’s disease (AD) pathology, was found elevated in plasma but not in cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). We expanded...

Classification of Alzheimer's disease based on hippocampal multivariate morphometry statistics.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, and mild cognitive impairment (MCI) is associated with a high risk of developing AD. Hippocampal morphometry analysis is believed to be the most robust magnetic resonance imaging (MRI) markers for AD and MCI. Multivariate morphometry statistics (MMS), a quantitative method of surface deformations analysis, is confirmed to have strong statistical power for evaluating hippocampus. We aimed to test whether surface deformation features in hippocampus can be employed for early classification of AD, MCI, and healthy controls (HC). We first explored the differences in hippocampus surface deformation among these three groups by using MMS analysis. Additionally, the hippocampal MMS features of selective patches and support vector machine (SVM) were used for the binary classification and triple classification. By the results, we identified significant hippocampal deformation among the three groups, especially in hippocampal CA1. In addition, the binary classification of AD/HC, MCI/HC, AD/MCI showed good performances, and area under curve (AUC) of triple-classification model achieved 0.85. Finally, positive correlations were found between the hippocampus MMS features and cognitive performances. The study revealed significant hippocampal deformation among AD, MCI, and HC. Additionally, we confirmed that hippocampal MMS can be used as a sensitive imaging biomarker for the early diagnosis of AD at the individual level.

Alzheimer’s Disease and Premature Ovarian Insufficiency

Estradiol promotes neuronal growth, transmission, survival, myelinization, plasticity, synaptogenesis, and dendritic branching and it improves cognitive function. Alzheimer’s disease (AD) is characterized by amyloid plaques, neurofibrillary tangles, and the loss of neuronal connection in the brain. Genomic analysis has concluded that hypoestrogenism influences the APOE gene and increases the risk of AD. Premature ovarian insufficiency (POI) is defined as oligo/amenorrhea in women below 40 years of age, low estradiol, and high-gonadotropin levels. Early symptoms and signs of POI must be detected in time in order to prevent subsequent complications, such as Alzheimer’s disease. Meta-analysis has shown favorable effects of estrogen in preventing Alzheimer’s. We measured some of the typical markers of AD in women with POI such as interleukin 6 (IL-6), interleukin 8 (IL-8), tissue necrosis factor α (TNFα), TAU1, TREM2, and amyloid precursor proteins (APP). While FSH, LH, and IL-8 were significantly higher in POI group, compared to controls, testosterone and DHEAS were lower. A significant decrease in IL-6 was found in the POI group during a 6-month therapy, as well as an increase in amyloid precursor proteins. CONCLUSION: Neurological complications of POI, such as declining short-term memory, cognitive function, and dementia, have to be promptly stopped by initiating estro-progestogen therapy in POI. A long-term continuation of the therapy would be strongly advised.

Detecting amyloid-β positivity using regions of interest from structural magnetic resonance imaging.

Alzheimer disease (AD) is the most common type of dementia. Amyloid-β (Aβ) positivity is the main diagnostic marker for AD. Aβ positron emission tomography and cerebrospinal fluid are widely used in the clinical diagnosis of AD. However, these methods only assess the concentrations of Aβ, and the accessibility of these methods is thus relatively limited compared with structural magnetic resonance imaging (sMRI). We investigated whether regions of interest (ROIs) in sMRIs can be used to predict Aβ positivity for samples with normal cognition (NC), mild cognitive impairment (MCI), and dementia. We obtained 846 Aβ negative (Aβ-) and 865 Aβ positive (Aβ+) samples from the Alzheimer's Disease Neuroimaging Initiative database. To predict which samples are Aβ+, we built five machine learning models using ROIs and apolipoprotein E (APOE) genotypes as features. To test the performance of the machine learning models, we constructed a new cohort containing 97 Aβ- and 81 Aβ+ samples. The best performing machine learning model combining ROIs and APOE had an accuracy of 0.798, indicating that it can help predict Aβ+. Furthermore, we searched ROIs that could aid our prediction and discovered that an average left entorhinal cortical region (L-ERC) thickness is an important feature. We also noted significant differences in L-ERC thickness between the Aβ- and Aβ+ samples even in the same diagnosis of NC, MCI, and dementia. Our findings indicate that ROIs from sMRIs along with APOE can be used as an initial screening tool in the early diagnosis of AD.

Tau, β-Amyloid, and Glucose Metabolism Following Service-Related Traumatic Brain Injury in Vietnam War Veterans: The Australian Imaging Biomarkers and Lifestyle Study of Aging-Veterans Study (AIBL-VETS).

Traumatic brain injury (TBI) is common among military veterans and has been associated with an increased risk of dementia. It is unclear if this is due to increased risk for Alzheimer's disease (AD) or other mechanisms. This case control study sought evidence for AD, as defined by the 2018 National Institute on Aging - Alzheimer's Association (NIA-AA) research framework, by measuring tau, β-amyloid, and glucose metabolism using positron emission tomography (PET) in veterans with service-related TBI. Seventy male Vietnam war veterans-40 with TBI (age 68.0 ± 2.5 years) and 30 controls (age 70.1 ± 5.3 years)-with no prior diagnosis of dementia or mild cognitive impairment underwent β-amyloid (18F-Florbetaben), tau (18F-Flortaucipir), and fluorodeoxyglucose (18F-FDG) PET. The TBI cohort included 15 participants with mild, 16 with moderate, and nine with severe injury. β-Amyloid level was calculated using the Centiloid (CL) method and tau was measured by standardized uptake value ratios (SUVRs) using the cerebellar cortex as reference region. Analyses were adjusted for age and APOE-e4. The findings were validated in an independent cohort from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DOD ADNI) study. There were no significant nor trending differences in β-amyloid or tau levels or 18F-FDG uptake between the TBI and control groups before and after controlling for covariates. The β-amyloid and tau findings were replicated in the DOD ADNI validation cohort and persisted when the Australian Imaging Biomarkers and Lifestyle study of aging-Veterans study (AIBL-VETS) and DOD ADNI cohorts were combined (114 TBI vs. 87 controls in total). In conclusion, no increase in the later life accumulation of the neuropathological markers of AD in veterans with a remote history of TBI was identified.

Biomarkers Assessing Endothelial Dysfunction in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common degenerative disorder in the elderly in developed countries. Currently, growing evidence is pointing at endothelial dysfunction as a key player in the cognitive decline course of AD. As a main component of the blood-brain barrier (BBB), the dysfunction of endothelial cells driven by vascular risk factors associated with AD allows the passage of toxic substances to the cerebral parenchyma, producing chronic hypoperfusion that eventually causes an inflammatory and neurotoxic response. In this process, the levels of several biomarkers are disrupted, such as an increase in adhesion molecules that allow the passage of leukocytes to the cerebral parenchyma, increasing the permeability of the BBB; moreover, other vascular players, including endothelin-1, also mediate artery inflammation. As a consequence of the disruption of the BBB, a progressive neuroinflammatory response is produced that, added to the astrogliosis, eventually triggers neuronal degeneration (possibly responsible for cognitive deterioration). Recently, new molecules have been proposed as early biomarkers for endothelial dysfunction that can constitute new therapeutic targets as well as early diagnostic and prognostic markers for AD.

Functional and structural alterations of dorsal attention network in preclinical and early-stage Alzheimer's disease.

Subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are known as the preclinical and early stage of Alzheimer's disease (AD). The dorsal attention network (DAN) is mainly responsible for the "top-down" attention process. However, previous studies mainly focused on single functional modality and limited structure. This study aimed to investigate the multimodal alterations of DAN in SCD and aMCI to assess their diagnostic value in preclinical and early-stage AD. Resting-state functional magnetic resonance imaging (MRI) was carried out to measure the fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and functional connectivity (FC). Structural MRI was used to calculate the gray matter volume (GMV) and cortical thickness. Moreover, receiver-operating characteristic (ROC) analysis was used to distinguish these alterations in SCD and aMCI. The SCD and aMCI groups showed both decreased ReHo in the right middle temporal gyrus (MTG) and decreased GMV compared to healthy controls (HCs). Especially in the SCD group, there were increased fALFF and increased ReHo in the left inferior occipital gyrus (IOG), decreased fALFF and increased FC in the left inferior parietal lobule (IPL), and reduced cortical thickness in the right inferior temporal gyrus (ITG). Furthermore, functional and structural alterations in the SCD and aMCI groups were closely related to episodic memory (EM), executive function (EF), and information processing speed (IPS). The combination of multiple indicators of DAN had a high accuracy in differentiating clinical stages. Our current study demonstrated functional and structural alterations of DAN in SCD and aMCI, especially in the MTG, IPL, and SPL. Furthermore, cognitive performance was closely related to these significant alterations. Our study further suggested that the combined multiple indicators of DAN could be acted as the latent neuroimaging markers of preclinical and early-stage AD for their high diagnostic value.

Blood biomarkers in mild cognitive impairment patients: Relationship between analytes and progression to Alzheimer disease dementia.

Blood-based biomarkers are promising tools for the diagnosis of Alzheimer disease (AD) at prodromal stages (mild cognitive impairment [MCI]) and are hoped to be implemented as screening tools for patients with cognitive complaints. In this work, we evaluated the potential of peripheral neurological biomarkers to predict progression to AD dementia and the relation between blood and cerebrospinal fluid (CSF) AD markers in MCI patients referred from a general neurological department. A group of 106 MCI patients followed at the Neurology Department of Coimbra University Hospital was included. Data regarding baseline neuropsychological evaluation, CSF levels of amyloid β 42 (Aβ42), Aβ40, total tau (t-Tau), and phosphorylated tau 181 (p-Tau181) were available for all the patients. Aβ42, Aβ40, t-Tau, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) levels were determined in baseline stored serum and plasma samples by commercial SiMoA (Single Molecule Array) assays. Progression from MCI to AD dementia was assessed at follow-up (mean=5.8± 3.4 years). At baseline, blood markers NfL, GFAP, and p-Tau181 were significantly increased in patients who progressed to AD at follow-up (p< 0.001). In contrast, plasma Aβ42/40 ratio and t-Tau showed no significant differences between groups. NfL, GFAP, and p-Tau181 demonstrated good diagnostic accuracy to identify progression to AD dementia (area under the curve [AUC]=0.81, 0.80, and 0.76, respectively), which improved when combined (AUC=0.89). GFAP and p-Tau181 were correlated with CSF Aβ42. Association of p-Tau181 with NfL was mediated by GFAP, with a significant indirect association of 88% of the total effect. Our findings highlight the potential of combining blood-based GFAP, NfL, and p-Tau181 to be applied as a prognostic tool in MCI.

Characterization of Cystatin B Interactome in Saliva from Healthy Elderly and Alzheimer's Disease Patients.

Cystatin B is a small, multifunctional protein involved in the regulation of inflammation, innate immune response, and neuronal protection and found highly abundant in the brains of patients with Alzheimer's disease (AD). Recently, our study demonstrated a significant association between the level of salivary cystatin B and AD. Since the protein is able to establish protein-protein interaction (PPI) in different contexts and aggregation-prone proteins and the PPI networks are relevant for AD pathogenesis, and due to the relevance of finding new AD markers in peripheral biofluids, we thought it was interesting to study the possible involvement of cystatin B in PPIs in saliva and to evaluate differences and similarities between AD and age-matched elderly healthy controls (HC). For this purpose, we applied a co-immunoprecipitation procedure and a bottom-up proteomics analysis to purify, identify, and quantify cystatin B interactors. Results demonstrated for the first time the existence of a salivary cystatin B-linked multi-protein complex composed by 82 interactors and largely expressed in the body. Interactors are involved in neutrophil activation, antimicrobial activity, modulation of the cytoskeleton and extra-cellular matrix (ECM), and glucose metabolism. Preliminary quantitative data showed significantly lower levels of triosophosphate isomerase 1 and higher levels of mucin 7, BPI, and matrix Gla protein in AD with respect to HC, suggesting implications associated with AD of altered glucose metabolism, antibacterial activities, and calcification-associated processes. Data are available via ProteomeXchange with identifiers PXD039286 and PXD030679.

Sex-specific effects of ethanol consumption in older Fischer 344 rats on microglial dynamics and Aβ(1-42) accumulation.

Chronic alcohol consumption, Alzheimer's disease (AD), and vascular dementia are all associated with cognitive decline later in life, raising questions about whether their underlying neuropathology may share some common features. Indeed, recent evidence suggests that ethanol exposure during adolescence or intermittent drinking in young adulthood increased neuropathological markers of AD, including both tau phosphorylation and beta-amyloid (Aβ) accumulation. The goal of the present study was to determine whether alcohol consumption later in life, a time when microglia and other neuroimmune processes tend to become overactive, would influence microglial clearance of Aβ(1-42), focusing specifically on microglia in close proximity to the neurovasculature. To do this, male and female Fischer 344 rats were exposed to a combination of voluntary and involuntary ethanol consumption from ∼10 months of age through ∼14 months of age. Immunofluorescence revealed profound sex differences in microglial co-localization, with Aβ(1-42) showing that aged female rats with a history of ethanol consumption had a higher number of iba1+ cells and marginally reduced expression of Aβ(1-42), suggesting greater phagocytic activity of Aβ(1-42) among females after chronic ethanol consumption later in life. Interestingly, these effects were most prominent in Iba1+ cells near neurovasculature that was stained with tomato lectin. In contrast, no significant effects of ethanol consumption were observed on any markers in males. These findings are among the first reports of a sex-specific increase in microglia-mediated phagocytosis of Aβ(1-42) by perivascular microglia in aged, ethanol-consuming rats, and may have important implications for understanding mechanisms of cognitive decline associated with chronic drinking.

Challenges and opportunities of diagnostic markers of Alzheimer's disease based on structural magnetic resonance imaging.

This article aimed to carry out a narrative literature review of early diagnostic markers of Alzheimer's disease (AD) based on both micro and macro levels of pathology, indicating the shortcomings of current biomarkers and proposing a novel biomarker of structural integrity that associates the hippocampus and adjacent ventricle together. This could help to reduce the influence of individual variety and improve the accuracy and validity of structural biomarker. This review was based on presenting comprehensive background of early diagnostic markers of AD. We have compiled those markers into micro level and macro level, and discussed the advantages and disadvantages of them. Eventually the ratio of gray matter volume to ventricle volume was put forward. The costly methodologies and related high patient burden of "micro" biomarkers (cerebrospinal fluid biomarkers) hinder the implementation in routine clinical examination. In terms of "macro" biomarkers- hippocampal volume (HV), there is a large variation of it among population, which undermines its validity Considering the gray matter atrophies while the adjacent ventricular volume enlarges, we assume the hippocampal to ventricle ratio (HVR) is a more reliable marker than HV alone the emerging evidence showed hippocampal to ventricle ratio predicts memory functions better than HV alone in elderly sample. The ratio between gray matter structures and adjacent ventricular volumes counts as a promising superior diagnostic marker of early neurodegeneration.

Greater subjective cognitive decline severity is associated with worse memory performance and lower entorhinal cerebral blood flow in healthy older adults.

Subjective cognitive decline (SCD) is a potential early risk marker for Alzheimer's disease (AD), but its utility may vary across individuals. We investigated the relationship of SCD severity with memory function and cerebral blood flow (CBF) in areas of the middle temporal lobe (MTL) in a cognitively normal and overall healthy sample of older adults. Exploratory analyses examined if the association of SCD severity with memory and MTL CBF was different in those with lower and higher cardiovascular disease (CVD) risk status. Fifty-two community-dwelling older adults underwent magnetic resonance imaging, neuropsychological testing, and were administered the Everyday Cognition Scale (ECog) to measure SCD. Regression models investigated whether ECog scores were associated with memory performance and MTL CBF, followed by similar exploratory regressions stratified by CVD risk status (i.e., lower vs higher stroke risk). Higher ECog scores were associated with lower objective memory performance and lower entorhinal cortex CBF after adjusting for demographics and mood. In exploratory stratified analyses, these associations remained significant in the higher stroke risk group only. Our preliminary findings suggest that SCD severity is associated with cognition and brain markers of preclinical AD in otherwise healthy older adults with overall low CVD burden and that this relationship may be stronger for individuals with higher stroke risk, although larger studies with more diverse samples are needed to confirm these findings. Our results shed light on individual characteristics that may increase the utility of SCD as an early risk marker of cognitive decline.

27-hydroxycholesterol promotes oligodendrocyte maturation: Implications for hypercholesterolemia-associated brain white matter changes.

Oxidized cholesterol metabolite 27-hydroxycholesterol (27-OH) is a potential link between hypercholesterolemia and neurodegenerative diseases since unlike peripheral cholesterol, 27-OH is transported across the blood-brain barrier. However, the effects of high 27-OH levels on oligodendrocyte function remain unexplored. We hypothesize that during hypercholesterolemia 27-OH may impact oligodendrocytes and myelin and thus contribute to the disconnection of neural networks in neurodegenerative diseases. To test this idea, we first investigated the effects of 27-OH in cultured oligodendrocytes and found that it induces cell death of immature O4+ /GalC+ oligodendrocytes along with stimulating differentiation of PDGFR+ oligodendrocyte progenitors (OPCs). Next, transgenic mice with increased systemic 27-OH levels (Cyp27Tg) underwent behavioral testing and their brains were immunohistochemically stained and lysed for immunoblotting. Chronic exposure to 27-OH in mice resulted in increased myelin basic protein (MBP) but not 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) or myelin oligodendrocyte glycoprotein (MOG) levels in the corpus callosum and cerebral cortex. Intriguingly, we also found impairment of spatial learning suggesting that subtle changes in myelinated axons of vulnerable areas like the hippocampus caused by 27-OH may contribute to impaired cognition. Finally, we found that 27-OH levels in cerebrospinal fluid from memory clinic patients were associated with levels of the myelination regulating CNPase, independently of Alzheimer's disease markers. Thus, 27-OH promotes OPC differentiation and is toxic to immature oligodendrocytes as well as it subtly alters myelin by targeting oligodendroglia. Taken together, these data indicate that hypercholesterolemia-derived higher 27-OH levels change the oligodendrocytic capacity for appropriate myelin remodeling which is a crucial factor in neurodegeneration and aging.