Subjective cognitive decline domain improves accuracy of plasma Aβ_(42)/Aβ_(40)for preclinical Alzheimer’s disease diagnosis:The SILCODE study

To the Editor:Accumulating evidence has shown that the preclinical stage of Alzheimer’s disease(AD)(i.e.,asymptomatic amyloidosis)lasts for decades before the onset of cognitive symptoms,providing a large window for early intervention.Amyloid pathology,the earliest pathological change associated with AD,can be detected in vivo with cerebrospinal fluid(CSF)analysis or positron emission tomography(PET),and its presence is necessary for the diagnosis of preclinical AD(pre-AD).However,both PET scans and CSF analyses are expensive,hampering their use in large-scale screening.Thus,blood-based biomarkers are desirable alternatives,as they are cost-effective and not invasive.

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.

Progress in blood biomarkers of subjective cognitive decline in preclinical Alzheimer’s disease

Alzheimer's disease(AD)is a neurodegenerative disease that gradually impairs cognitive functions.Recently,there has been a conceptual shift toward AD to view the disease as a continuum.Since AD is currently incurable,effective intervention to delay or prevent pathological cognitive decline may best target the early stages of symptomatic disease,such as subjective cognitive decline(SCD),in which cognitive function remains relatively intact.Diagnostic methods for identifying AD,such as cerebrospinal fluid biomarkers and positron emission tomography,are invasive and expensive.Therefore,it is imperative to develop blood biomarkers that are sensitive,less invasive,easier to access,and more cost effective for AD diagnosis.This review aimed to summarize the current data on whether individuals with SCD differ reliably and effectively in subjective and objective performances compared to cognitively normal elderly individuals,and to find one or more convenient and accessible blood biomarkers so that researchers can identify SCD patients with preclinical AD in the population as soon as possible.Owing to the heterogeneity and complicated pathogenesis of AD,it is difficult to make reliable diagnoses using only a single blood marker.This review provides an overview of the progress achieved to date with the use of SCD blood biomarkers in patients with preclinical AD,highlighting the key areas of application and current challenges.

Genetic Phenotypes of Alzheimer’s Disease:Mechanisms and Potential Therapy

Years of intensive research has brought us extensive knowledge on the genetic and molecular factors involved in Alzheimer's disease(AD).In addition to the mutations in the three main causative genes of familial AD(FAD)including presenilins and amyloid precursor protein genes,studies have identified several genes as the most plausible genes for the onset and progression of FAD,such as triggering receptor expressed on myeloid cells 2,sortilin-related receptor 1,and adenosine triphosphate-binding cassette transporter subfamily A member 7.The apolipoprotein Eε4 allele is reported to be the strongest genetic risk factor for sporadic AD(SAD),and it also plays an important role in FAD.Here,we reviewed recent developments in genetic and molecular studies that contributed to the understanding of the genetic phenotypes of FAD and compared them with SAD.We further reviewed the advancements in AD gene therapy and discussed the future perspectives based on the genetic phenotypes.

Storage time affects the level and diagnostic efficacy of plasma biomarkers for neurodegenerative diseases

Several promising plasma biomarker proteins,such as amyloid-β(Aβ),tau,neurofilament light chain,and glial fibrillary acidic protein,are widely used for the diagnosis of neurodegenerative diseases.However,little is known about the long-term stability of these biomarker proteins in plasma samples stored at-80°C.We aimed to explore how storage time would affect the diagnostic accuracy of these biomarkers using a large cohort.Plasma samples from 229 cognitively unimpaired individuals,encompassing healthy controls and those experiencing subjective cognitive decline,as well as 99 patients with cognitive impairment,comprising those with mild cognitive impairment and dementia,were acquired from the Sino Longitudinal Study on Cognitive Decline project.These samples were stored at-80°C for up to 6 years before being used in this study.Our results showed that plasma levels of Aβ42,Aβ40,neurofilament light chain,and glial fibrillary acidic protein were not significantly correlated with sample storage time.However,the level of total tau showed a negative correlation with sample storage time.Notably,in individuals without cognitive impairment,plasma levels of total protein and tau phosphorylated protein threonine 181(p-tau181)also showed a negative correlation with sample storage time.This was not observed in individuals with cognitive impairment.Consequently,we speculate that the diagnostic accuracy of plasma p-tau181 and the p-tau181 to total tau ratio may be influenced by sample storage time.Therefore,caution is advised when using these plasma biomarkers for the identification of neurodegenerative diseases,such as Alzheimer's disease.Furthermore,in cohort studies,it is important to consider the impact of storage time on the overall results.

Impaired Parahippocampal Gyrus-Orbitofrontal Cortex Circuit Associated with Visuospatial Memory Deficit as a Potential Biomarker and Interventional Approach for Alzheimer Disease

The parahippocampal gyrus-orbitofrontal cortex(PHG-OFC)circuit in humans is homologous to the postrhinal cortex(POR)-ventral lateral orbitofrontal cortex(vlOFC)circuit in rodents.Both are associated with visuospatial malfunctions in Alzheimer’s disease(AD).However,the underlying mechanisms remain to be elucidated.In this study,we explored the relationship between an impaired POR-vlOFC circuit and visuospatial memory deficits through retrograde tracing and in vivo local field potential recordings in 5XFAD mice,and investigated alterations of the PHG-OFC circuit by multi-domain magnetic resonance imaging(MRI)in patients on the AD spectrum.We demonstrated that an impaired glutamatergic POR-vlOFC circuit resulted in deficient visuospatial memory in 5XFAD mice.Moreover,MRI measurements of the PHG-OFC circuit had an accuracy of 77.33%for the classification of amnestic mild cognitive impairment converters versus non-converters.Thus,the PHG-OFC circuit explains the neuroanatomical basis of visuospatial memory deficits in AD,thereby providing a potential predictor for AD progression and a promising interventional approach for AD.

Towards Personalized Intervention for Alzheimer's Disease

Alzheimer＇s disease （AD） remains to be a grand challenge for the international community despite over a century of exploration. A key factor likely accounting for such a situation is the vast heterogeneity in the disease etiology, which involves very complex and divergent pathways. Therefore, intervention strategies shall be tailored for subgroups of AD patients. Both demographic and in-depth information is needed for patient stratification. The demographic information includes primarily APOE genotype, age, gender, education, environmental exposure, life style, and medical history, whereas in-depth information stems from genome sequencing, brain imaging, peripheral biomarkers, and even functional assays on neurons derived from patient-specific induced pluripotent cells （iPSCs）. Comprehensive information collection, better understanding of the disease mech- anisms, and diversified strategies of drug development would help with more effective intervention in the foreseeable future.

Critical thinking of Alzheimer's transgenic mouse model:current research and future perspective

Transgenic models are useful tools for studying the pathogenesis of and drug development for Alzheimer's Disease(AD).AD models are constructed usually using overexpression or knock-in of multiple pathogenic gene mutations from familial AD.Each transgenic model has its unique behavioral and pathological features.This review summarizes the research progress of transgenic mouse models,and their progress in the unique mechanism of amyloid-βoligomers,including the first transgenic mouse model built in China based on a single gene mutation(PSEN1 V97L)found in Chinese familial AD.We further summarized the preclinical findings of drugs using the models,and their future application in exploring the upstream mechanisms and multi-target drug development in AD.

The Role of Frontal and Occipital Cortices in Processing Sustained Visual Attention in Young Adults with Attention-Deficit/Hyperactivity Disorder:A Functional Near-Infrared Spectroscopy Study

Dear Editor,Attention deficit/hyperactivity disorder(ADHD),characterized by age-inappropriate symptoms of inattention,hyperactivity,and impulsivity,is a highly prevalent and heritable childhood-onset neurodevelopmental disorder,with impairing symptoms that persist into adulthood in up to 65%of patients[1].Adults with persistent ADHD symptoms since childhood have been found to have neurocognitive impairments in multiple domains,especially in attention and cognitive control,which significantly contribute to an increased risk of social disability,educational and occupational failure,and other comorbid psychiatric disorders,resulting in significant economic burdens to the affected individuals, their families, andsociety [2, 3].

Genomics in Neurological Disorders

Neurological disorders comprise a variety of complex diseases in the central nervous system, which can be roughly classified as neurodegenerative diseases and psychiatric disorders. The basic and translational research of neurological disorders has been hindered by the difficulty in accessing the pathological center （i.e., the brain） in live patients. The rapid advancement of sequencing and array technologies has made it possible to investigate the disease mechanism and biomarkers from a systems perspective. In this review, recent progresses in the discovery of novel risk genes, treatment targets and peripheral biomarkers employing genomic technologies will be dis- cussed. Our major focus will be on two of the most heavily investigated neurological disorders, namely Alzheimer＇s disease and autism spectrum disorder.

阿尔茨海默病多中心独立的、可重复的海马影像组学标志物:早期识别、纵向进展和生物学基础

脑内海马结构的形态学变化是阿尔茨海默病(AD)的影像学标记之一.海马的影像组学特征是否可以作为AD早期识别的生物标记以及是否可以预测轻度认知损害(MCI)的转化尚需进一步验证,并且海马影像组学特征是否有其神经生物学基础也需要进一步探索.本文的主要目的是研究海马的影像组学特征是否可以作为AD早期识别的影像学标记.为此,我们利用最常用的多变量分类器对AD(261例)和正常人(231例)进行独立中心识别的交叉验证,6个中心的平均准确率为88.21%,更进一步,利用完全独立的ADNI数据集(1228例被试)也验证了这一结果.通过对MCI人群的系统研究发现,部分重要海马影像组学特征与被试的生物学评分(主要包括APOE基因型、多基因风险分数、脑脊液的生物标记物Aβ和Tau,以及认知能力的变化等)具有显著的相关性.更为重要的是,通过5年左右的纵向跟踪研究发现影像组学特征的变化与认知水平的变化具有高度一致性.本研究结果表明海马的影像组学特征有希望用于早期识别AD,具有预测MCI病人是否会转化为AD的潜在能力.综上,研究结果将有可能应用于MCI和AD的早期辅助识别,具有重要的临床意义.

阿尔茨海默病现状及展望

Aging is an undeniable fact of life and the global population is aging to a historically unprecedented degree. The population aged65 years or older comprises 750 million people, representing nearly 10%of the global population. As a result of prolonged life expectancy and falling mortality rates, China has become one of the most rapidly aging countries in the world, even surpassing several high-income countries in North America and Europe.