Decoding the diagnostic potential of T cell repertoires in peripheral blood of patients from amnestic mild cognitive impairment to Alzheimer's disease.

Alzheimer's disease (AD) is currently an incurable neurodegenerative disorder and is the most common etiological cause of dementia. Consequently, it has severe burden on its patients and on their caregivers and represents a global health concern. Clinical investigations have indicated that a dysregulation of peripheral T cell immune homeostasis may be involved in the pathogenesis of AD, as well as in the early stages of AD, characterized by mild cognitive impairment (MCI). However, the characteristics and concomitant feasibility of the use of T-cell receptor (TCR) typing for disease diagnosis remains largely unknown. We employed a high-throughput sequencing and multidimensional bioinformatics analyses for the identification of TCR repertoires present in peripheral blood samples of 10 patients with amnestic MCI (aMCI), 10 patients with AD, and 10 healthy controls (HCs). Based on the characteristics of the TCR repertoires in the amount and diversity of combinations of V-J, the spectrum of immune defense, and differentially expressed genes (DEGs), single and specific TCR profiles were observed in the patient samples of aMCI and AD compared to profiles of HCs. In particular, the diversity of TCR clonotypes manifested a pattern of "decreased first and then increased" pattern during the progression from aMCI to AD, a pattern that was not observed in HC samples. Additionally, a total of 46 and 35 amino acid CDR3 sequences with consistent and reverse expressive abundance with diversity of TCR clonotypes were identified, respectively. Taken together, we provide novel and essential preliminary evidence demonstrating the presence of diversity of T cell repertoires from differentially expressed V-J gene segments and amino acid clonotypes using peripheral blood samples from patients with AD, aMCI, and from HC. Such findings have the potential to reveal potential mechanisms through which aMCI progresses to AD and provide a reference for the future development of immune-related diagnoses and therapies for AD.

Neuroticism polygenic risk predicts conversion from mild cognitive impairment to Alzheimer's disease by impairing inferior parietal surface area.

The high prevalence of conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) makes early prevention of AD extremely critical. Neuroticism, a heritable personality trait associated with mental health, has been considered a risk factor for conversion from aMCI to AD. However, whether the neuroticism genetic risk could predict the conversion of aMCI and its underlying neural mechanisms is unclear. Neuroticism polygenic risk score (N-PRS) was calculated in 278 aMCI patients with qualified genomic and neuroimaging data from ADNI. After 1-year follow-up, N-PRS in patients of aMCI-converted group was significantly greater than those in aMCI-stable group. Logistic and Cox survival regression revealed that N-PRS could significantly predict the early-stage conversion risk from aMCI to AD. These results were well replicated in an internal dataset and an independent external dataset of 933 aMCI patients from the UK Biobank. One sample Mendelian randomization analyses confirmed a potentially causal association from higher N-PRS to lower inferior parietal surface area to higher conversion risk of aMCI patients. These analyses indicated that neuroticism genetic risk may increase the conversion risk from aMCI to AD by impairing the inferior parietal structure.

Tai Chi-Induced Exosomal LRP1 is Associated With Memory Function and Hippocampus Plasticity in aMCI Patients.

OBJECTIVES: The study was designed to identify the potential peripheral processes of circulating exosome in response to Tai Chi (TC) exercise and the possibility of its loaded cargos in mediating the effects of TC training on cognitive function among older adults with amnestic mild cognitive impairment (aMCI). DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter randomized controlled trial. One hundred community-dwelling old adults with aMCI were randomly assigned (1:1) to experimental (n = 50) and control groups (n = 50). INTERVENTION: The experimental group participated in TC exercise 5 times/week, with each session lasting 60 minutes for 12 weeks. Both experimental and control groups received health education every 4 weeks. MEASUREMENTS: The primary outcome was global cognitive function. Neurocognitive assessments, MRI examination, and large-scale proteomics analysis of peripheric exosome were conducted at baseline and after 12-week training. Outcome assessors and statisticians were blinded to group allocation. RESULTS: A total of 96 participants (96%) completed all outcome measurements. TC training improved global cognitive function (adjusted mean difference [MD] = 1.9, 95%CI 0.93-2.87, p <0.001) and memory (adjusted MD = 6.42, 95%CI 2.09-10.74, p = 0.004), increased right hippocampus volume (adjusted MD = 88.52, 95%CI 13.63-163.4, p = 0.021), and enhanced rest state functional connectivity (rsFC) between hippocampus and cuneus, which mediated the group effect on global cognitive function (bootstrapping CIs: [0.0208, 1.2826], [0.0689, 1.2211]) and verbal delay recall (bootstrapping CI: [0.0002, 0.6277]). Simultaneously, 24 differentially expressed exosomal proteins were detected in tandem mass tag-labelling proteomic analysis. Of which, the candidate protein low-density lipoprotein receptor-related protein 1 (LRP1) was further confirmed by parallel reaction monitoring and ELISA. Moreover, the up-regulated LRP1 was both positively associated with verbal delay recall and rsFC (left hippocampus-right cuneus). CONCLUSION: TC promotes LRP1 release via exosome, which was associated with enhanced memory function and hippocampus plasticity in aMCI patients. Our findings provided an insight into potential therapeutic neurobiological targets focusing on peripheric exosome in respond to TC exercise.

Functional gradients reveal altered functional segregation in patients with amnestic mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease and amnestic mild cognitive impairment are associated with disrupted functional organization in brain networks, involved with alteration of functional segregation. Connectome gradients are a new tool representing brain functional topological organization to smoothly capture the human macroscale hierarchy. Here, we examined altered topological organization in amnestic mild cognitive impairment and Alzheimer's disease by connectome gradient mapping. We further quantified functional segregation by gradient dispersion. Then, we systematically compared the alterations observed in amnestic mild cognitive impairment and Alzheimer's disease patients with those in normal controls in a two-dimensional functional gradient space from both the whole-brain level and module level. Compared with normal controls, the first gradient, which described the neocortical hierarchy from unimodal to transmodal regions, showed a more distributed and significant suppression in Alzheimer's disease than amnestic mild cognitive impairment patients. Furthermore, gradient dispersion showed significant decreases in Alzheimer's disease at both the global level and module level, whereas this alteration was limited only to limbic areas in amnestic mild cognitive impairment. Notably, we demonstrated that suppressed gradient dispersion in amnestic mild cognitive impairment and Alzheimer's disease was associated with cognitive scores. These findings provide new evidence for altered brain hierarchy in amnestic mild cognitive impairment and Alzheimer's disease, which strengthens our understanding of the progressive mechanism of cognitive decline.

Distinct Patterns of Brain Atrophy in Amnestic Mild Cognitive Impairment and Motoric Cognitive Risk Syndromes.

INTRODUCTION: Motoric cognitive risk (MCR) and amnestic mild cognitive impairment (aMCI) syndromes are each reliable predictors of incident Alzheimer's disease (AD), but MCR may be a stronger predictor of vascular dementia than AD. This study contrasted cortical and hippocampal atrophy patterns in MCR and aMCI. METHODS: Cross-sectional data from 733 older adults without dementia or disability (M age = 73.6; 45% women) in the multicountry MCR consortium were examined. MCR was defined as presence of slow gait and cognitive concerns. Amnestic MCI was defined as poor episodic memory performance and cognitive concerns. Cortical thickness and hippocampal volumes were quantified from structural MRIs. Multivariate and univariate general linear models were used to examine associations between cortical thickness and hippocampal volume in MCR and aMCI, adjusting for age, sex, education, total intracranial volume, white matter lesions, and study site. RESULTS: The prevalence of MCR and aMCI was 7.64% and 12.96%, respectively. MCR was associated with widespread cortical atrophy, including prefrontal, insular, cingulate, motor, parietal, and temporal atrophy. aMCI was associated with hippocampal atrophy. CONCLUSION: Distinct patterns of atrophy were associated with MCR and aMCI. A distributed pattern of cortical atrophy - that is more consistent with VaD or mixed dementia- was observed in MCR. A more restricted pattern of atrophy - that is more consistent with AD - was observed in aMCI. The biological underpinnings of MCR and aMCI likely differ and may require tailored interventions.

fNIRS as a biomarker for individuals with subjective memory complaints and MCI.

INTRODUCTION: Identifying individuals at risk of developing dementia is crucial for early intervention. Mild cognitive impairment (MCI) and subjective memory complaints (SMCs) are considered its preceding stages. This study aimed to assess the utility of functional near-infrared spectroscopy (fNIRS) in identifying individuals with MCI and SMC. METHODS: One hundred fifty-one participants were categorized into normal cognition (NC); amnestic MCI (aMCI); non-amnestic MCI (naMCI); and mild, moderate, and severe SMC groups. Task-related prefrontal hemodynamics were measured using fNIRS during a visual memory span task. RESULTS: Results showed significantly lower oxyhemoglobin (HbO) levels in aMCI, but not in naMCI, compared to the NC. In addition, severe SMC had lower HbO levels than the NC, mild, and moderate SMC. Receiver operating characteristic analysis demonstrated 69.23% and 69.70% accuracy in differentiating aMCI and severe SMC from NC, respectively. DISCUSSION: FNIRS may serve as a potential non-invasive biomarker for early detection of dementia. HIGHLIGHTS: Only amnestic mild cognitive impairment (aMCI), but not non-amnestic MCI, showed lower oxyhemoglobin (HbO) than normal individuals. Reduced HbO was observed in those with severe subjective memory complaints (SMCs) compared to normal cognition (NC), mild, and moderate SMCs. Functional near-infrared spectroscopy measures were associated with performance in memory assessments. Prefrontal hemodynamics could distinguish aMCI and severe SMC from NC.

Visual search in Alzheimer's disease and amnestic mild cognitive impairment: An eye-tracking study.

INTRODUCTION: Visual search impairment is a potential cognitive marker for Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). The aim of this study is to compare eye movements during visual tracking in AD and aMCI patients versus healthy controls (HCs). METHODS: A prospective cohort study included 32 AD and 37 aMCI patients, and 33 HCs. Each participant was asked to look at the target object in a visual stimulus containing one target and eight distractors, and eye movements were recorded with EyeLink 1000 Plus. RESULTS: AD patients had fewer fixations and shorter target fixation duration than aMCI patients and HCs. Fixation durations were also shorter in aMCI patients compared to HCs. Also, AD patients were more fixated on distractors than HCs. DISCUSSION: Our findings revealed that visual search is impaired in the early stages of AD and even aMCI, highlighting the importance of addressing visual processes in the Alzheimer's continuum. HIGHLIGHTS: AD patients looked to distractors more and longer than the target compared to aMCI patients and older healthy individuals. aMCI patients had an impaired visual search pattern compared to healthy controls, just like patients with AD. The visual search task differentiated AD and aMCI patients from healthy individuals without dementia.

The moderating role of information processing speed in the relationship between brain remodeling and episodic memory in amnestic mild cognitive impairment.

INTRODUCTION: The role of information processing speed (IPS) on relationships between episodic memory (EM) and central remodeling features in amnestic mild cognitive impairment (aMCI) was investigated. METHODS: Neuropsychological evaluations and multimodal magnetic resonance imaging were performed on 48 patients diagnosed with aMCI and 50 healthy controls (HC). Moderation models explored the moderating effect of IPS on associations between EM and imaging features at single-region, connectivity, and network levels. RESULTS: IPS significantly enhanced the positive correlations between recall and cortical thickness of left inferior temporal gyrus. IPS also notably amplified negative correlations between recognition and functional connectivity (FC) of left inferior parietal lobe and right occipital, as well as between recall/recognition and nodal clustering coefficient of left anterior cingulate cortex. DISCUSSION: IPS functioned as a moderator of associations between recall and neuroimaging metrics at the "single region-connectivity-network" level, providing new insights for cognitive rehabilitation in aMCI patients. HIGHLIGHTS: aMCI patients exhibited brain functional and structural remodeling alterations. IPS moderated relations between episodic memory and brain remodeling metrics. Therapy targeted at IPS can be considered for improving episodic memory in aMCI.

Brain network dynamics in patients with single- and multiple-domain amnestic mild cognitive impairment.

INTRODUCTION: Brain network dynamics have been extensively explored in patients with amnestic mild cognitive impairment (aMCI); however, differences in single- and multiple-domain aMCI (SD-aMCI and MD-aMCI) remain unclear. METHODS: Using multicenter datasets, coactivation patterns (CAPs) were constructed and compared among normal control (NC), SD-aMCI, MD-aMCI, and Alzheimer's disease (AD) patients based on individual high-order cognitive network (HOCN) and primary sensory network (PSN) parcellations. Correlations between spatiotemporal characteristics and neuropsychological scores were analyzed. RESULTS: Compared to NC, SD-aMCI showed temporal alterations in HOCN-dominant CAPs, while MD-aMCI showed alterations in PSN-dominant CAPs. In addition, transitions from SD-aMCI to AD may involve PSN, while MD-aMCI to AD involves both PSN and HOCN. Results were generally consistent across datasets from Chinese and White populations. DISCUSSION: The HOCN and PSN are distinctively involved in aMCI subtypes and in the transformation between aMCI subtypes and AD, highlighting the necessity of aMCI subtype classification in AD studies. HIGHLIGHTS: Individual functional network parcellations and coactivation pattern (CAP) analysis were performed to characterize spatiotemporal differences between single- and multiple-domain amnestic mild cognitive impairment (SD-aMCI and MD-aMCI), and between distinct aMCI subtypes and Alzheimer's disease (AD). The analysis of multicenter datasets converged on four pairs of recurrent CAPs, including primary sensory networks (PSN)-dominant CAPs, high-order cognitive networks (HOCN)-dominant CAPs, and PSN-HOCN-interacting CAPs. The HOCN and PSN are distinctively involved in aMCI subtypes and in the transformation between distinct aMCI subtypes and AD.

Machine learning-based classification of Alzheimer's disease and its at-risk states using personality traits, anxiety, and depression.

BACKGROUND: Alzheimer's disease (AD) is often preceded by stages of cognitive impairment, namely subjective cognitive decline (SCD) and mild cognitive impairment (MCI). While cerebrospinal fluid (CSF) biomarkers are established predictors of AD, other non-invasive candidate predictors include personality traits, anxiety, and depression, among others. These predictors offer non-invasive assessment and exhibit changes during AD development and preclinical stages. METHODS: In a cross-sectional design, we comparatively evaluated the predictive value of personality traits (Big Five), geriatric anxiety and depression scores, resting-state functional magnetic resonance imaging activity of the default mode network, apoliprotein E (ApoE) genotype, and CSF biomarkers (tTau, pTau181, Aß42/40 ratio) in a multi-class support vector machine classification. Participants included 189 healthy controls (HC), 338 individuals with SCD, 132 with amnestic MCI, and 74 with mild AD from the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). RESULTS: Mean predictive accuracy across all participant groups was highest when utilizing a combination of personality, depression, and anxiety scores. HC were best predicted by a feature set comprised of depression and anxiety scores and participants with AD were best predicted by a feature set containing CSF biomarkers. Classification of participants with SCD or aMCI was near chance level for all assessed feature sets. CONCLUSION: Our results demonstrate predictive value of personality trait and state scores for AD. Importantly, CSF biomarkers, personality, depression, anxiety, and ApoE genotype show complementary value for classification of AD and its at-risk stages.

Sex-dependent changes in emotional memory associated with cerebral blood flow alterations during Alzheimer's disease progression.

PURPOSE: Sex differences in Alzheimer's disease (AD) progression provide clues to pathogenesis and better patient management. We examined sex differences in emotional memory among AD patients, amnestic mild cognitive impairment (aMCI) patients, and healthy controls (HCs) as well as potential associations with altered regional cerebral blood flow (rCBF). METHODS: The recognition memory task with emotional pictures was applied to evaluate enhancement of emotional memory (EEM) and 3D pseudo-continuous arterial spin labeling MRI was performed to measure the rCBF in 74 AD patients (41 females), 74 aMCI patients (45 females), and 74 HCs (43 females). Group differences in EEM were tested by two-way analysis of covariance (ANCOVA) with repeated measures. The main effects of clinical group and sex as well as group × sex interactions on rCBF were assessed by two-way ANCOVA. Correlation analyses were conducted to investigate associations between EEM and rCBF. RESULTS: With disease progression, EEM gradually disappeared. Among aMCI patients, females exhibited a greater index of recollection (Pr) for positive/high-arousal and negative/low-arousal pictures versus neutral pictures (P = 0.005, P = 0.003), while males exhibited a greater Pr for negative/high-arousal versus neutral pictures (P = 0.001). There were significant sex × group effects on rCBF in left inferior parietal, supramarginal, superior temporal and middle temporal gyri, and rCBF of left inferior parietal gyrus was correlated with Pr for positive/high-arousal pictures among female aMCI patients (r = 0.584, q = 0.005). CONCLUSION: Males and females exhibit distinct changes in EEM associated with altered rCBF, which should be considered in future neuroimaging studies.

Co-expression network analysis of frontal cortex during the progression of Alzheimer's disease.

Mechanisms of Alzheimer's disease (AD) and its putative prodromal stage, amnestic mild cognitive impairment (aMCI), involve the dysregulation of multiple candidate molecular pathways that drive selective cellular vulnerability in cognitive brain regions. However, the spatiotemporal overlap of markers for pathway dysregulation in different brain regions and cell types presents a challenge for pinpointing causal versus epiphenomenal changes characterizing disease progression. To approach this problem, we performed Weighted Gene Co-expression Network Analysis and STRING interactome analysis of gene expression patterns quantified in frontal cortex samples (Brodmann area 10) from subjects who died with a clinical diagnosis of no cognitive impairment, aMCI, or mild/moderate AD. Frontal cortex was chosen due to the relatively protracted involvement of this region in AD, which might reveal pathways associated with disease onset. A co-expressed network correlating with clinical diagnosis was functionally associated with insulin signaling, with insulin (INS) being the most highly connected gene within the network. Co-expressed networks correlating with neuropathological diagnostic criteria (e.g., NIA-Reagan Likelihood of AD) were associated with platelet-endothelium-leucocyte cell adhesion pathways and hypoxia-oxidative stress. Dysregulation of these functional pathways may represent incipient alterations impacting disease progression and the clinical presentation of aMCI and AD.

Cingulate white matter mediates the effects of fecal Ruminococcus on neuropsychiatric symptoms in patients with amyloid-positive amnestic mild cognitive impairment.

BACKGROUND: Microbiota-gut-brain axis interacts with one another to regulate brain functions. However, whether the impacts of gut dysbiosis on limbic white matter (WM) tracts contribute to the neuropsychiatric symptoms (NPS) in patients with amyloid-positive amnestic mild cognitive impairment (aMCI+), have not been explored yet. This study aimed to investigate the mediation effects of limbic WM integrity on the association between gut microbiota and NPS in patients with aMCI+. METHODS: Twenty patients with aMCI + and 20 healthy controls (HCs) were enrolled. All subjects underwent neuropsychological assessments and their microbial compositions were characterized using 16S rRNA Miseq sequencing technique. Amyloid deposition inspected by positron emission tomography imaging and limbic WM tracts (i.e., fornix, cingulum, and uncinate fasciculus) detected by diffusion tensor imaging were additionally measured in patients with aMCI+. We employed a regression-based mediation analysis using Hayes's PROCESS macro in this study. RESULTS: The relative abundance of genera Ruminococcus and Lactococcus was significantly decreased in patients with aMCI + versus HCs. The relative abundance of Ruminococcus was negatively correlated with affective symptom cluster in the aMCI + group. Notably, this association was mediated by WM integrity of the left cingulate gyrus. CONCLUSIONS: Our findings suggest Ruminococcus as a potential target for the management of affective impairments in patients with aMCI+.

Diagnostic Performance of a Tablet Computer-Based Cognitive Screening Test for Identification of Amnestic Mild Cognitive Impairment.

BACKGROUND: Early and appropriate diagnosis of amnestic mild cognitive impairment (aMCI) is clinically important because aMCI is considered the prodromal stage of dementia caused by Alzheimer's disease (AD). aMCI is assessed using the comprehensive neuropsychological (NP) battery, but it is rater-dependent and does not provide quick results. Thus, we investigated the performance of the computerized cognitive screening test (Inbrain Cognitive Screening Test; Inbrain CST) in the diagnosis of aMCI and compared its performance to that of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test (CERAD-K), a comprehensive and pencil-and-paper NP test. METHODS: A total of 166 participants were included in this cross-sectional study. The participants were recruited as part of a prospective, community-based cohort study for MCI (PREcision medicine platform for mild cognitive impairment on multi-omics, imaging, evidence-based R&BD; PREMIER). All participants were assessed using the CERAD-K and the Inbrain CST. The Inbrain CST comprised seven subtests that assessed the following five cognitive domains: attention, language, visuospatial, memory, and executive functions. Seventy-six participants underwent brain magnetic resonance imaging and [18F]-flutemetamol positron emission tomography (PET). We evaluated the diagnostic performance of the Inbrain CST for the identification of aMCI by comparing the findings with those of CERAD-K. We also determined the characteristics of aMCI patients as defined by the CERAD-K and Inbrain CST. RESULTS: Of the 166 participants, 93 were diagnosed with aMCI, while 73 were cognitively unimpaired. The sensitivity of the Inbrain CST for aMCI diagnosis was 81.7%, and its specificity was 84.9%. Positive and negative predictive values were 87.4% and 78.5%, respectively. The diagnostic accuracy was 83.1%, and the error rate was 16.9%. Demographic and clinical characteristics between individuals with aMCI defined by the Inbrain CST and CERAD-K were not significantly different. The frequency of positive amyloid PET scan, the hippocampal/parahippocampal volumes, and AD signature cortical thickness did not differ between the patients with aMCI defined by CERAD-K and those with aMCI defined by the Inbrain CST. CONCLUSION: The Inbrain CST showed sufficient sensitivity, specificity, and positive and negative predictive values for diagnosing objective memory impairment in aMCI. In addition, aMCI patients identified by CERAD-K and the Inbrain CST showed comparable clinical and neuroimaging characteristics. Therefore, the Inbrain CST can be considered an alternative test to supplement the limitations of existing pencil-and-paper NP tests.

Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Cancer History Avoids the Increase of Senescence Markers in Peripheral Cells of Amnestic Mild Cognitive Impaired Patients.

Epidemiological studies show that having a history of cancer protects from the development of Alzheimer's Disease (AD), and vice versa, AD protects from cancer. The mechanism of this mutual protection is unknown. We have reported that the peripheral blood mononuclear cells (PBMC) of amnestic cognitive impairment (aMCI) and Alzheimer's Disease (AD) patients have increased susceptibility to oxidative cell death compared to control subjects, and from the opposite standpoint a cancer history is associated with increased resistance to oxidative stress cell death in PBMCs, even in those subjects who have cancer history and aMCI (Ca + aMCI). Cellular senescence is a regulator of susceptibility to cell death and has been related to the pathophysiology of AD and cancer. Recently, we showed that cellular senescence markers can be tracked in PBMCs of aMCI patients, so we here investigated whether these senescence markers are dependent on having a history of cancer. Senescence-associated ßeta-galactosidase (SA-ß-Gal) activity, G0-G1 phase cell-cycle arrest, p16 and p53 were analyzed by flow cytometry; phosphorylated H2A histone family member X (γH2AX) by immunofluorescence; IL-6 and IL-8 mRNA by qPCR; and plasmatic levels by ELISA. Senescence markers that were elevated in PBMCs of aMCI patients, such as SA-ß-Gal, Go-G1 arrested cells, IL-6 and IL-8 mRNA expression, and IL-8 plasmatic levels, were decreased in PBMCs of Ca + aMCI patients to levels similar to those of controls or of cancer survivors without cognitive impairment, suggesting that cancer in the past leaves a fingerprint that can be peripherally traceable in PBMC samples. These results support the hypothesis that the senescence process might be involved in the inverse association between cancer and AD.

High-resolution NMR metabolomics of patients with subjective cognitive decline plus: Perturbations in the metabolism of glucose and branched-chain amino acids.

BACKGROUND: "Subjective cognitive decline plus" (SCD plus) increases the risk of Alzheimer's disease (AD), and this may be an early stage of AD that precedes amnestic mild cognitive impairment (aMCI). We examined alterations of serum metabolites and metabolic pathways in SCD plus subjects using 1H-magnetic resonance spectroscopy (1H NMR) metabolomics. METHODS: Serum samples from subjects with SCD plus (n = 32), aMCI (n = 33), and elderly controls (ECs, n = 41) were analyzed using an 800MHz NMR spectrometer. Multivariate analyses were used to identify serum metabolites, and two machine-learning methods were used to evaluate the diagnostic power of these metabolites in distinguishing SCD plus subjects, aMCI subjects, and ECs. RESULTS: Eight metabolites differentiated SCD plus from EC subjects. A random forest (RF) model discriminated SCD plus from EC subjects with an accuracy of 0.883 and an area under the receiver operating characteristic curve (AUROC) of 0.951. A support vector machine (SVM) model had an accuracy of 0.857 and an AUROC of 0.946. Nine other metabolites distinguished SCD plus from aMCI subjects. An RF model discriminated SCD plus from aMCI subjects (accuracy: 0.975, AUROC: 0.998) and an SVM model also discriminated these two groups (accuracy: 0.955, AUROC: 0.991). Disturbances of glucose and branched-chain amino acid (BCAA) metabolism were the most striking features of SCD plus subjects, and valine was positively correlated with Auditory Verbal Learning Test delayed-recall score. CONCLUSIONS: Serum metabolomics using 1H NMR provided noninvasive identification of perturbations in glucose and BCAA metabolism in subjects with SCD plus.

Speech silence character as a diagnostic biomarker of early cognitive decline and its functional mechanism: a multicenter cross-sectional cohort study.

BACKGROUND: Language deficits frequently occur during the prodromal stages of Alzheimer's disease (AD). However, the characteristics of linguistic impairment and its underlying mechanism(s) remain to be explored for the early diagnosis of AD. METHODS: The percentage of silence duration (PSD) of 324 subjects was analyzed, including patients with AD, amnestic mild cognitive impairment (aMCI), and normal controls (NC) recruited from the China multi-center cohort, and the diagnostic efficiency was replicated from the Pitt center cohort. Furthermore, the specific language network involved in the fragmented speech was analyzed using task-based functional magnetic resonance. RESULTS: In the China cohort, PSD increased significantly in aMCI and AD patients. The area under the curve of the receiver operating characteristic curves is 0.74, 0.84, and 0.80 in the classification of NC/aMCI, NC/AD, and NC/aMCI+AD. In the Pitt center cohort, PSD was verified as a reliable diagnosis biomarker to differentiate mild AD patients from NC. Next, in response to fluency tasks, clusters in the bilateral inferior frontal gyrus, precentral gyrus, left inferior temporal gyrus, and inferior parietal lobule deactivated markedly in the aMCI/AD group (cluster-level P < 0.05, family-wise error (FWE) corrected). In the patient group (AD+aMCI), higher activation level of the right pars triangularis was associated with higher PSD in in both semantic and phonemic tasks. CONCLUSIONS: PSD is a reliable diagnostic biomarker for the early stage of AD and aMCI. At as early as aMCI phase, the brain response to fluency tasks was inhibited markedly, partly explaining why PSD was elevated simultaneously.

Comparison of dynamic susceptibility contrast enhanced MR and FDG-PET brain studies in patients with Alzheimer's disease and amnestic mild cognitive impairment.

BACKGROUND: The aim of this study was to compare Dynamic Susceptibility Contrast Enhanced MRI (DSC-MRI) and PET with [18F]flurodeoxyglucose (FDG-PET) in the diagnosis of Alzheimer's Disease (AD) and amnestic Mild Cognitive Impairment (aMCI). METHODS: Twenty-seven age-and sex-matched patients with AD, 39 with aMCI and 16 controls underwent brain DSC-MRI followed by FDG-PET. Values of relative Cerebral Blood Volume (rCBV) and rCBV z-scores from frontal, temporal, parietal and PCG cortices were correlated with the rate of glucose metabolism from PET. Sensitivity, specificity and accuracy of DSC-MRI and FDG-PET in the diagnosis of AD and aMCI were assessed and compared. RESULTS: In AD, hypoperfusion was found within all the examined locations, while in aMCI in both parietal and temporal cortices and left PCG. FDG-PET showed the greatest hypometabolism in parietal, temporal and left PCG regions in both AD and aMCI. FDG-PET was more accurate in distinguishing aMCI from the controls than DSC-MRI. In the AD and combined group (AD + aMCI) there were numerous correlations between DSC-MRI and FDG-PET results. CONCLUSIONS: In AD the patterns of hypoperfusion and glucose hypometabolism are similar, thus DSC-MRI may be a competitive method to FDG-PET. FDG-PET is a more accurate method in the diagnosis of aMCI.

Long-term test-retest of cerebral [18F]MK-6240 binding and longitudinal evaluation of extracerebral tracer uptake in healthy controls and amnestic MCI patients.

PURPOSE: Neurofibrillary tangles (NFTs) in Alzheimer's disease can be accurately quantified in vivo using [18F]MK-6240 PET. Short-term [18F]MK-6240 test-retest (TRT) is about 6%, but also long-term stability of cerebral uptake is of importance for longitudinal studies. Furthermore, although there is very little cerebral off-target binding, [18F]MK-6240 shows variable extracerebral uptake (ECU) assumed to represent off-target binding to leptomeningeal melanocytes. Here, we examined 6-month TRT of [18F]MK-6240 in healthy controls (HC) and investigated ECU in HC and patients with amnestic mild cognitive impairment (aMCI) with up to 2 years of follow-up. We also explored demographic factors that may be associated to ECU, including age, sex, education, smoking, and disease status. METHODS: A total cohort of 40 HC (57 ± 19 years, 21F/19 M) and 24 aMCI (72 ± 8 years, 14F/10 M) underwent baseline [18F]MK-6240 PET-MR (GE Signa), 90-120 min post injection. [18F]MK-6240 was quantified by standardized uptake value ratios (SUVR) in predefined volumes-of-interest relative to the cerebellar cortex. Ten HC (56 ± 12 years, 8F/2 M) underwent a 6-month follow-up [18F]MK-6240 to assess TRT. Also, 10 aMCI (72 ± 6 years, 5F/5 M) underwent a 2-year follow-up [18F]MK-6240 PET-MR. Longitudinal changes in ECU were assessed in both cohorts. ECU was quantified as the mean SUVR of the skull parcel (FreeSurfer 6.0) that includes the meninges. RESULTS: The mean gray matter [18F]MK-6240 SUVR TRT and absolute TRT in HC were 1.6 ± 3.4% and 2.4 ± 2.8%, respectively. We found no significant 6-month or 2-year differences in ECU in HC (4.4 ± 20%) and aMCI (7.9 ± 19%), respectively. In the total cohort, ECU was significantly correlated to age (rs = - 0.48; p < 0.0001), and a multivariate analysis also showed sex differences (higher ECU in women). CONCLUSION: [18F]MK-6240 shows excellent 6-month TRT, which confirms its suitability for quantification of longitudinal NFT changes. The ECU of [18F]MK-6240 is variable between subjects, influenced by age and sex, but remains stable within subjects over a 2-year time period.