Decomposing the effect of normal aging and Alzheimer’s disease in brain morphological changes via learned aging templates

Decision letter: Stage-dependent differential influence of metabolic and structural networks on memory across Alzheimer’s disease continuum

Vulnerable Neural Systems and the Borderland of Brain Aging and Neurodegeneration

Traumatic brain injury (TBI) has been proposed as a risk factor for Alzheimer's disease (AD), although the mechanisms underlying the putative association are poorly understood. We investigated elderly individuals with a remote history of TBI, aiming to understand how this may have influenced amyloidosis, neurodegeneration, and clinical expression along the AD continuum. Total of 241 individual datasets including amyloid beta (Aβ) positron emission tomography ([18F]-AV45), structural MRI, and neuropsychological measures, were obtained from the Alzheimer's Disease Neuroimaging Initiative. The data were stratified into groups with (TBI +) or without (TBI-) history of head injury, and by clinical dementia rating (CDR) scores, into subgroups with normal cognition (CDR = 0) and those with symptomatic cognitive decline (CDR ≥ 0.5). We contrasted the TBI + and TBI- subgroups with respect to the onset age and extent of cognitive decline, cortical thickness changes, and Aβ standard uptake value (SUVr). Compared to the TBI-/CDR ≥ 0.5 subgroup, the TBI + /CDR ≥ 0.5 subgroup showed a 3-4year earlier age of cognitive impairment onset (ACIO, p = 0.005). Among those participants on the AD continuum (Aβ + , as defined by a cortical SUVr ≥ 1.23), irrespective of current CDR, a TBI + history was associated with greater Aβ deposition and more pronounced cortical thinning. When matched for severity of cognitive status, the TBI + /CDR ≥ 0.5 group showed greater Aβ burden, but earlier ACIO as compared to the TBI-/CDR ≥ 0.5, suggesting a more indolent clinical AD progression in those with TBI history. Remote TBI history may alter the AD onset trajectory, with approximately 4years earlier ACIO, greater amyloid deposition, and cortical thinning.

BackgroundPlasma biomarker has the potential to be the reliable and propagable approach in the early stage diagnosis of Alzheimer’s disease (AD). However, conventional methods appear powerless in the detection of these biomarkers at low concentrations in plasma. Here, we determined plasma biomarker concentrations of patients across the AD spectrum by an improved digital enzyme-linked immunosorbent assay (ELISA) technique. Confirms the predictive and diagnostic value of this method for AD patients and study the relationships between these biomarkers and cognitive status.MethodsPlasma concentrations of amyloid-beta 40 (Aβ40), amyloid-beta 42 (Aβ42) and plasma phosphorylated tau at threonine 181 (p-tau181) were determined in 43 AD patients, 33 mild cognitive impairment (MCI) patients and 40 normal cognition (NC) subjects as healthy controls using the improved digital ELISA technique. In addition, all subjects were required to receive neuropsychological assessments.ResultsPlasma p-tau181 level showed certain discrepancies between NC and MCI (p < 0.05), AD (p < 0.01) groups. The level of plasma Aβ42 (p < 0.05) and Aβ40 (p < 0.01) was significantly different between AD and NC group. The p-tau181 level was able to distinguish AD (AUC = 0.8768) and MCI (AUC = 0.7932) from NC with higher accuracy than Aβ42/Aβ40 ratio (AUC = 0.8343, AUC = 0.6569). Both p-tau181 (CDR: r = 0.388 p < 0.001; MMSE: r = −0.394 p < 0.001) and Aβ42/Aβ40 ratio (CDR: r = −0.413 p < 0.001; MMSE: r = 0.358 p < 0.001) showed stronger positive correlation with clinical dementia rating (CDR) and mini mental state examination (MMSE) scores than Aβ42 (CDR: r = −0.280 p = 0.003; MMSE: r = 0.266 p = 0.005) or Aβ40 (CDR: r = 0.373 p < 0.001; MMSE: r = −0.288 p = 0.002) alone.ConclusionPlasma p-tau181 level and Aβ42/Aβ40 ratio showed promising values in diagnosis of AD and MCI. Our results indicate that this improved digital ELISA diagnosis approach can facilitate early recognition and management of AD and pre-AD patients.

To the Editor: Alzheimer disease (AD) is the most common form of dementia, and the central pathogenic event is the abnormal accumulation of amyloid β–protein (Aβ) in extracellular amyloid deposits and cerebral blood vessels.1 AD is a complex and genetically heterogeneous disease. Mild cognitive impairment (MCI), a cognitive disorder in the transition between normal cognition and AD, is a known risk factor for AD, with a conversion rate of ≈10% per year.2 Apolipoprotein E (apoE), a lipid transporter, has been found to be contained in amyloid plaques. The apoE4 isoform or APOE e4 allele is associated with the development of AD1 and an increased risk of MCI.3 Cholesterol has also been identified as a risk factor for AD1,4 and MCI.5 A direct role of cholesterol in the pathogenesis of AD has been suggested by studies in transgenic animal models of AD: cholesterol feeding increases Aβ accumulation and accelerates AD-related pathology,6 whereas cholesterol lowering with statin reduces Aβ pathology.7 Although CAD is a prevalent finding in AD,8 whether or not plasma lipoprotein subfractions are associated with MCI and AD has not yet been investigated. The separation and determination of lipoprotein subfractions are generally labor-intensive and time-consuming. Recently, however, the research group of Schmitz and coworkers developed a new automated technique to separate and quantify lipoprotein subfractions in minutes using capillary isotachophoresis (cITP).9,10 Therefore, in the present study, we investigated the associations among lipoprotein subfractions as determined by cITP, apoE phenotype, MCI, and AD. Twenty-eight patients with MCI, 47 patients with AD, and 26 nondemented control subjects were evaluated at the Neurology Department of Fukuoka …

This study aimed to determine the neuropsychological differences between patients with early-stage Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) with a Clinical Dementia Rating (CDR) score of ≤1. We examined 168 patients with AD (126 with CDR score=0.5, 42 with CDR score=1) and 169 patients with DLB (104 with CDR score=0.5, 65 with CDR score=1) whose diagnoses were supported by 18F-flobetaben positron-emission tomography (PET) and 18F-N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane PET. Neuropsychological test scores were compared after controlling for age, sex, and education duration. Using a cutoff motor score on the Unified Parkinson's Disease Rating Scale of 20, patients with AD were further divided into AD with parkinsonism (ADP+, n=86) and AD without parkinsonism (ADP-, n=82). At CDR scores of both 0.5 and 1, the DLB group had lower scores on the attention (digit-span forward at CDR score=0.5 and backward at CDR score=1), visuospatial, and executive (color reading Stroop test at CDR score=0.5 and phonemic fluency test, Stroop tests, and digit symbol coding at CDR score=1) tests than the AD group, but higher scores on the memory tests. The ADP- and ADP+ subgroups had comparable scores on most neuropsychological tests, but the ADP+ subgroup had lower scores on the color reading Stroop test. Patients with DLB had worse attention, visuospatial, and executive functions but better memory function than patients with AD. Parkinsonism was not uncommon in the patients with AD and could be related to attention and executive dysfunction.

BackgroundA disintegrin and metalloproteinase 17 (ADAM-17) has multiple pathophysiological functions in Alzheimer's disease (AD). However, the clinical relevance of ADAM-17 in AD is not clear yet.ObjectiveThis study aims to investigate the levels of circulating ADAM-17 and their association with AD.MethodsThis cross-sectional study recruited 40 normal cognition (NC) participants and 36 AD patients. Plasma ADAM-17 and biomarkers of neurodegeneration were determined. The association of plasma ADAM-17 with cognitive functions and biomarkers of neurodegeneration was analyzed.ResultsPlasma ADAM-17 levels were elevated in AD patients in comparison with NC subjects. Plasma ADAM-17 was positively associated with Clinical Dementia Rating (CDR) scores, but negatively associated with the Mini-Mental State Examination scores and Montreal Cognitive Assessment scores. Plasma ADAM-17 levels were positively associated with the levels of Aβ40, Aβ42, and p-Tau181.ConclusionsThese findings suggest a link between ADAM-17 and the pathogenesis of AD from a clinical perspective.

Different patterns of hypoperfusion in frontotemporal dementia and Alzheimer’s disease by arterial spin labeling MRI

Magnetic resonance imaging (MRI)-based volumetric measurements of medial temporal lobe (MTL) structures can discriminate between normal elderly control subjects and patients with Alzheimer's disease (AD) of moderate to advanced severity. In terms of clinical utility, however, a more important issue concerns the ability of the technique to differentiate between normal elderly control subjects and AD patients with the very mildest form of the disease. We performed MRI-based volumetric measurements of the hippocampus, parahippocampal gyrus, and amygdala in 126 cognitively normal elderly control subjects and 94 patients with probable AD. The diagnosis of AD was made according to NINDS/ADRDA criteria, and disease severity was categorized by Clinical Dementia Rating (CDR) scores. Patients with CDR 0.5 were classified as very mild, CDR 1 as mild, and CDR 2 as moderate disease severity. Volumes of each structure declined with increasing age in control subjects and did so in parallel for men and women. The volume of each measured MTL structure also declined with age in patients with AD. The volume of each MTL structure was significantly smaller in AD patients than control subjects (p < 0.001). Of the several MTL measures, the total hippocampal volumetric measurements were best at discriminating control subjects from AD patients. The mean hippocampal volumes for AD patients relative to control subjects by severity of disease were as follows: very mild AD (CDR 0.5) -1.75 SD below the control mean, mild AD (CDR 1) -1.99 SD, and moderate AD (CDR 2) -2.22 SD. Age- and gender-adjusted, normalized MRI-based hippocampal volumetric measurements provide a sensitive marker of the MTL neuroanatomic degeneration in AD early in the disease process.

Hippocampal volume change over time, measured with MRI, has huge potential as a marker for Alzheimer's disease. The objectives of this study were: (i) to test if constant and accelerated hippocampal loss can be detected in Alzheimer's disease, mild cognitive impairment and normal ageing over short periods, e.g. 6–12 months, with MRI in the large multicentre setting of the Alzheimer's Disease Neuroimaging Initiative (ADNI); (ii) to determine the extent to which the polymorphism of the apolipoprotein E (ApoE) gene modulates hippocampal change; and (iii) to determine if rates of hippocampal loss correlate with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, such as the β-amyloid (Aβ1–42) and tau proteins (tau). The MRI multicentre study included 112 cognitive normal elderly individuals, 226 mild cognitive impairment and 96 Alzheimer's disease patients who all had at least three successive MRI scans, involving 47 different imaging centres. The mild cognitive impairment and Alzheimer's disease groups showed hippocampal volume loss over 6 months and accelerated loss over 1 year. Moreover, increased rates of hippocampal loss were associated with presence of the ApoE allele ɛ4 gene in Alzheimer's disease and lower CSF Aβ1–42 in mild cognitive impairment, irrespective of ApoE genotype, whereas relations with tau were only trends. The power to measure hippocampal change was improved by exploiting correlations statistically between successive MRI observations. The demonstration of considerable hippocampal loss in mild cognitive impairment and Alzheimer's disease patients over only 6 months and accelerated loss over 12 months illustrates the power of MRI to track morphological brain changes over time in a large multisite setting. Furthermore, the relations between faster hippocampal loss in the presence of ApoE allele ɛ4 and decreased CSF Aβ1–42 supports the concept that increased hippocampal loss is an indicator of Alzheimer's disease pathology and a potential marker for the efficacy of therapeutic interventions in Alzheimer's disease.

Fil: Surace, Ezequiel Ignacio. Fundacion para la Lucha Contra las Enfermedades Neurologicas de la Infancia. Instituto de Investigaciones Neurologicas "Raul Carrea"; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas; Argentina

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

BackgroundNeuropathologically confirmed Alzheimer disease (AD) patients are heterogeneous in their cognitive functions, brain atrophy patterns, and neuropathological traits. Genetic risk profiles informed by brain proteome signatures may predict the conversion of clinically normal individuals to AD.MethodWe discovered co‐expressed proteome networks using 201 AD brains from the prefrontal cortex area in the Religious Orders Study and Memory and Aging Project (ROSMAP) and validated the findings using 328 AD brains in the Emory study. Of the preserved modules, we selected modules with significant association (P&lt;0.01) between neuropathologically and clinically confirmed AD (symptomatic) and neuropathologically confirmed AD but clinically unimpaired brains. We generated polygenic risk scores of the symptom‐associated modules (mbPRSs) using existing genome‐wide summary statistics for AD (Kunkle, 2019) in 309 AD, 483 mild cognitive impairment (MCI), and 301 cognitively normal (CN) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We investigated relationships between the derived mbPRSs and previously clustered brain atrophy patterns in the ADNI (Yang, 2021). We defined at‐risk CN and MCI subjects in the ADNI for each module if mbPRSs of the subject &gt; the third quantile. Age‐adjusted Cox proportional hazard models were applied for conversion status to AD with at‐risk subjects of the symptom‐associated modules comparing with all CN and MCI subjects as a reference group.ResultWe detected 12 preserved modules that showed significant associations for symptomatic AD (P‐value&lt;0.05). The mbPRSs of the yellow and the lightcyan modules were significantly associated with brain atrophy cluster 3 (P‐value: yellow‐mbPRS = 5.5e‐03; lightcyan‐mbPRS = 7.1e‐05). At the same time, Of the mbPRSs for the 12 symptom‐associated modules, the at‐risk subjects defined by the lightcyan‐mbPRS were also predicted to be earlier conversion from CN or MCI to AD (Hazard ratio = 1.63, P‐value = 3.8e‐02). Lightcyan‐mbPRS shows a good prediction of conversion to AD and also the association with MRI endophenotypes.ConclusionThis study demonstrates for the first time that PRSs informed by symptom‐associated protein networks may identify at‐risk CN and MCI subjects who will develop clinical symptoms and enable targeted prevention and treatment trials for AD for these at‐risk subjects in preclinical stages of AD.

Editor's evaluation: Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study

Decision letter: Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study