Preclinical Alzheimer's Disease Patients Research Articles

Disruptions of Gut Microbiota are Associated with Cognitive Deficit of Preclinical Alzheimer's Disease: A Cross-Sectional Study.

Alzheimer's Disease (AD) is the most prevalent type of dementia. The early change of gut microbiota is a potential biomarker for preclinical AD patients. The study aimed to explore changes in gut microbiota characteristics in preclinical AD patients, including those with Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI), and detect the correlation between gut microbiota characteristics and cognitive performances. This study included 117 participants [33 MCI, 54 SCD, and 30 Healthy Controls (HC)]. We collected fresh fecal samples and blood samples from all participants and evaluated their cognitive performance. We analyzed the diversity and structure of gut microbiota in all participants through qPCR, screened characteristic microbial species through machine learning models, and explored the correlations between these species and cognitive performances and serum indicators. Compared to the healthy controls, the structure of gut microbiota in MCI and SCD patients was significantly different. The three characteristic microorganisms, including Bacteroides ovatus, Bifidobacterium adolescentis, and Roseburia inulinivorans, were screened based on the best classification model (HC and MCI) having intergroup differences. Bifidobacterium adolescentis is associated with better performance in multiple cognitive scores and several serum indicators. Roseburia inulinivorans showed negative correlations with the scores of the Functional Activities Questionnaire (FAQ). The gut microbiota in patients with preclinical AD has significantly changed in terms of composition and richness. Correlations have been discovered between changes in characteristic species and cognitive performances. Gut microbiota alterations have shown promise in affecting AD pathology and cognitive deficit.

The electrophysiological and neuropathological profiles of cerebellum in APPswe /PS1ΔE9 mice: A hypothesis on the role of cerebellum in Alzheimer's disease.

We propose the hypothesis that the cerebellar electrophysiology and sleep-wake cycles may be altered at the early stage of Alzheimer's disease (AD), proceeding the amyloid-β neuropathological hallmarks. The electrophysiologic characteristics of cerebellum thereby might be served as a biomarker in the prepathological detection of AD. Sleep disturbances are common in preclinical AD patients, and the cerebellum has been implicated in sleep-wake regulation by several pioneer studies. Additionally, recent studies suggest that the structure and function of the cerebellum may be altered at the early stages of AD, indicating that the cerebellum may be involved in the disease's progression. We used APPswe /PS1ΔE9 mice as a model of AD, monitored and analyzed electroencephalogram data, and assessed neuropathological profiles in the cerebellum of AD mice. Our hypothesis may establish a linkage between the cerebellum and AD, thereby potentially providing new perspectives on the pathogenesis of the disease.

A Strategy for Discovery and Verification of Candidate Biomarkers in Cerebrospinal Fluid of Preclinical Alzheimer's Disease.

Alzheimer’s disease (AD), a progressive neurodegenerative disease, is characterized by the accumulation of senile plaques, neurofibrillary tangles, and loss of synapses and neurons in the brain. The pathophysiological process of AD begins with a long asymptomatic phase, which provides a potential opportunity for early therapeutic intervention. Therefore, it is crucial to define putative biomarkers via reliable and validated methods for early diagnosis of AD. Here, we characterized candidate biomarkers by discovery proteomics analysis of cerebrospinal fluid (CSF), revealing that 732 and 704 proteins with more than one unique peptide were identified in healthy controls and preclinical AD patients, respectively. Among them, 79 and 98 proteins were significantly altered in preclinical AD for women and men, respectively, many of which have been demonstrated with consistent regulation pattern in patients with mild cognitive impairment or AD dementia. In-house developed 5-plex isotopic N,N-dimethyl leucine (iDiLeu) tags were further utilized to verify candidate biomarkers, neurosecretory protein VGF (VGF) and apolipoprotein E (apoE). By labeling peptide standards with different iDiLeu tags, a four-point internal calibration curve was constructed to allow for determination of the absolute amount of target analytes in CSF through a single liquid chromatography-mass spectrometry run.

β-Amyloid Accumulation Slows Earlier than Expected in Preclinical Alzheimer's Disease Patients

Alzheimer's disease (AD) is the most common form of dementia, and epidemiological studies suggest that the rates of incidence will increase in the next decades ([Prince et al., 2013][1]). Clinically, AD is manifested by progressive memory loss, but the main pathophysiological hallmarks include

Auditory Verbal Learning Test is Superior to Rey-Osterrieth Complex Figure Memory for Predicting Mild Cognitive Impairment to Alzheimer's Disease.

To carry out meaningful comparisons on results of different research studies on mild cognitive impairment (MCI), it is critical to select an appropriate objective memory test to examine memory deficit. We aim to refine the operational criteria of amnestic MCI (aMCI) on neuropsychological tests that optimally balance the sensitivity and specificity. We focused on 206 non-demented subjects from memory clinic. We then classified each individual as having MCI or subjective cognitive decline (SCD) according to different neuropsychological criteria. By following them longitudinally, clinical outcomes were compared to evaluate the stability of MCI diagnoses and prediction of progression. The delayed recall of auditory verbal learning test (AVLT_DR) identified 116 subjects as MCI, resulted in the conversion rate as 44% over the roughly 30-month time interval, missed 7.8% incipient Alzheimer's disease (AD) patients in SCD group who eventually converted to dementia. The delayed recall of complex figure test (CFT_DR) identified fewer MCI patients (n=95) and misdiagnosed more preclinical AD patients (15.3%), in comparison with AVLT criterion. Criterion requiring deficits in both tests produced higher conversion rate (54.3%), but resulted in higher misdiagnosis rate (14.7%) simultaneously. The AVLT criterion had the largest area under the curve (0.7248, p<0.05). AVLT is superior to CFT in the stability of diagnoses and prediction of progression. In the clinical setting, the "one test" criterion AVLT has similar sensitivity to both-deficits methods, and is optimal in balancing sensitivity and specificity.

Partial eNOS deficiency causes spontaneous thrombotic cerebral infarction, amyloid angiopathy and cognitive impairment.

BackgroundCerebral infarction due to thrombosis leads to the most common type of stroke and a likely cause of age-related cognitive decline and dementia. Endothelial nitric oxide synthase (eNOS) generates NO, which plays a crucial role in maintaining vascular function and exerting an antithrombotic action. Reduced eNOS expression and eNOS polymorphisms have been associated with stroke and Alzheimer’s disease (AD), the most common type of dementia associated with neurovascular dysfunction. However, direct proof of such association is lacking. Since there are no reports of complete eNOS deficiency in humans, we used heterozygous eNOS+/- mice to mimic partial deficiency of eNOS, and determine its impact on cerebrovascular pathology and perfusion of cerebral vessels.ResultsCombining cerebral angiography with immunohistochemistry, we found thrombotic cerebral infarctions in eNOS+/- mice as early as 3–6 months of age but not in eNOS+/+ mice at any age. Remarkably, vascular occlusions in eNOS+/- mice were found almost exclusively in three areas: temporoparietal and retrosplenial granular cortexes, and hippocampus this distribution precisely matching the hypoperfused areas identified in preclinical AD patients. Moreover, progressive cerebral amyloid angiopaphy (CAA), blood brain barrier (BBB) breakdown, and cognitive impairment were also detected in aged eNOS+/- mice.ConclusionsThese data provide for the first time the evidence that partial eNOS deficiency results in spontaneous thrombotic cerebral infarctions that increase with age, leading to progressive CAA and cognitive impairments. We thus conclude that eNOS+/- mouse may represent an ideal model of ischemic stroke to address early and progressive damage in spontaneously-evolving chronic cerebral ischemia and thus, study vascular mechanisms contributing to vascular dementia and AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0020-0) contains supplementary material, which is available to authorized users.

Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by β-amyloid plaques and intraneuronal τ aggregation usually associated with cerebral amyloid angiopathy (CAA). Both β-amyloid plaques and CAA deposits contain fibrillar aggregates of the amyloid β-peptide (Aβ). Aβ plaques and CAA develop first in neocortical areas of preclinical AD patients and, then, expand in a characteristic sequence into further brain regions with end-stage pathology in symptomatic AD patients. Aβ aggregates are not restricted to amyloid plaques and CAA. Soluble and several types of insoluble non-plaque- and non-CAA-associated Aβ aggregates have been described. Amyloid fibrils are products of a complex self-assembly process that involves different types of transient intermediates. Amongst these intermediate species are protofibrils and oligomers. Different variants of Aβ peptides may result from alternative processing or from mutations that lead to rare forms of familial AD. These variants can exhibit different self-assembly and aggregation properties. In addition, several post-translational modifications of Aβ have been described that result, for example, in the production of N-terminal truncated Aβ with pyroglutamate modification at position 3 (AβN3pE) or of Aβ phosphorylated at serine 8 (pSer8Aβ). Both AβN3pE and pSer8Aβ show enhanced aggregation into oligomers and fibrils. However, the earliest detectable soluble and insoluble Aβ aggregates in the human brain exhibit non-modified Aβ, whereas AβN3pE and pSer8Aβ are detected in later stages. This finding indicates the existence of different biochemical stages of Aβ aggregate maturation with pSer8Aβ being related mainly to cases with symptomatic AD. The conversion from preclinical to symptomatic AD could thereby be related to combined effects of increased Aβ concentration, maturation of aggregates and spread of deposits into additional brain regions. Thus, the inhibition of Aβ aggregation and maturation before entering the symptomatic stage of the disease as indicated by the accumulation of pSer8Aβ may represent an attractive treatment strategy for preventing disease progression.

Ground zero in Alzheimer's disease

New findings in preclinical Alzheimer's disease patients and mouse models of the disease suggest that it is the lateral, rather than the medial, entorhinal cortex that is most susceptible to tau pathology early in Alzheimer's disease. Aberrations begin here and spread to other cortical sites.

Biomarkers and evolution in Alzheimer disease

Brain regions and their highly neuroplastic long axonal connections that expanded rapidly during hominid evolution are preferentially affected by Alzheimer disease. There is no natural animal model with full disease pathology (neurofibrillary tangles and neuritic amyloid plaques of a severity seen in Alzheimer's disease brains). Biomarkers such as reduced glucose metabolism in association neocortex, defects in long white matter tracts, RNA neurochemical changes, and high CSF levels of total and phosphorylated tau protein, which are helpful to identify MCI and preclinical Alzheimer disease patients, may also provide insights into what brain changes led to this disease being introduced during hominid evolution.

Role of By-Products of Lipid Oxidation in Alzheimer's Disease Brain: A Focus on Acrolein

Abundant data consistently support the idea that oxidative stress occurs and is a constant feature of Alzheimer's disease (AD). Some recent evidence indicated that phenomenon is an early event and might be implicated in the pathogenesis of this disease. Lipid peroxidation leads to the formation of a number of aldehydes by-products, including malondialdehyde (MDA), 4-hydroxy-2-nonenal (HNE), and acrolein. The most abundant aldehydes are HNE and MDA while acrolein is the most reactive. Increased levels of specific HNE-histidine and glutathione-HNE Michael adducts in AD brain has been reported. Proteomic analysis demonstrated a large number of protein-bound HNE in AD brain. F2-isoprostanes (F2-IsoPs) levels and neuroprostanes were also significantly increased in mild cognitive impairment (MCI) patients and in late-stage AD. In brain from patients with AD, acrolein has been found to be elevated in hippocampus and temporal cortex where oxidative stress is high. Due to its high reactivity, acrolein is not only a marker of lipid peroxidation but also an initiator of oxidative stress by adducting cellular nucleophilic groups found on proteins, lipids, and nucleic acids. Interestingly, data indicates that lipid peroxidation occurs in the brain of MCI and also in preclinical AD patients suggesting that oxidative damage may play an early role in the pathogenesis of AD. In this review, we will summarize some mechanisms implicated in the toxicity of by-products of lipid peroxidation such as IsoPs, HNE, and acrolein and their implication in AD.

The temporal localization of frame-shift ubiquitin-B and amyloid precursor protein, and complement proteins in the brain of non-demented control patients with increasing Alzheimer's disease pathology

Transcriptional misreading of dinucleotide repeats that generates deletions in RNA and produces frame-shift proteins with loss of function has been reported in Alzheimer's disease (AD). Here frame-shift ubiquitin-B and amyloid precursor protein were immunochemically shown to exist in the brain of high pathology control (HPC) patients with AD pathology but without prior dementia. These proteins were absent in low pathology control patients with limited AD pathology and no dementia. Since the HPC patients can be regarded as preclinical AD patients, our results suggest the accumulation of these proteins involved in the initial steps of AD pathogenesis. By contrast, complement proteins were detected in the AD patients, whereas only trace amounts were found in the HPC patients, indicating the involvement of complement proteins in the later stage of AD dementia.

Biological Markers of Alzheimer’s Disease

THREE major purposes for biological markers for Alzheimer's Disease (AD) have been suggested: diagnosis, treatment effect or progression, and prediction. Any potential marker must demonstrate sensitivity, specificity, reliability, and validity. A major obstacle to find a marker that fulfills these characteristics might be the long-term clinical and preclinical course of the disease. The duration of the clinical phase of the disease characterized by progressive cognitive decline is approximately 7 years from the occurence of first signs until death. It is assumed that the clinical phase is preceded by a 15-30-year preclinical period of continuous deposition of amyloid plaques and neurofibrillary tangles (and their constituent: paired helical filaments, PHF) (2,20). Figure I gives a schematic of a hypothetical model of the natural history of AD. Age of onset and rate of progression of the disease are largely determined by causative gene mutations and by genetic susceptibility factors. Several environmental risk factors may add to the individual genetic risk factors. If the assumption is true that a specific neuropathology precedes the clinical manifestation of the disease for years, or even decades, then a significant portion of the age-matched healthy controls may be preclinical AD patients. Therefore, when comparing AD patients to age-matched healthy controls using in vivo measures that are associated with the development of the specific histopathology of AD, a considerable overlap with age-matched healthy controls is to be expected.