Journal of Alzheimer's Disease最新文献

Background: Blood tests for Alzheimer's disease (AD) that measure biomarkers related to neuropathology have demonstrated to be useful, minimally-invasive ways to identify patients for screening into clinical trials. While some AD biomarkers can be detected in plasma, greater sensitivity is needed to make plasma AD tests more effective. Extracellular vesicles (EVs) in plasma carry AD-related biomarkers from the brain and could offer a concentrated source of brain-related biomarkers, though the methodological complexities involved in isolating plasma EVs have hampered its validation for clinical use.

Objective: To explore the feasibility and effectiveness of developing blood tests for AD utilizing extracellular vesicle-bound protein biomarkers.

Methods: We developed a simplified method for isolating EVs directly from plasma using an alternating current electrokinetic (ACE) microchip. No sample pretreatment steps were needed. Protein biomarkers on the EVs were detected by adding fluorescent antibodies to the plasma samples before capture by the chip. This allowed measurement of EV biomarker levels directly on the chip.

Results: AD or non-AD control plasma was measured for ten different AD-related biomarkers. EV-associated NCAM1, pTau231, α-synuclein, and TDP-43 levels were able to distinguish a group of 10 AD, 10 mild cognitive impairment (MCI), and 10 non-AD subjects. pTau231 was different between AD and non-AD (p = 0.0300) and α-synuclein differentiated AD from MCI (p = 0.0148).

Conclusions: This study shows how ACE microfluidic chip technology can help differentiate AD and MCI patients from non-AD controls with clinical relevance. This work also highlights the important diagnostic role of plasma EV biomarkers in neurodegenerative disease.

Background: Alzheimer's disease (AD) is characterized by progressive cognitive decline, including impairments in speech production and fluency. Mild cognitive impairment (MCI), a prodrome of AD, has also been linked with changes in speech behavior but to a more subtle degree.

Objective: This study aimed to investigate whether speech behavior immediately following both filled and unfilled pauses (post-pause speech behavior) differs between individuals with MCI and healthy controls (HCs), and how these differences are influenced by the cognitive demands of various speech tasks.

Methods: Transcribed speech samples were analyzed from both groups across different tasks, including immediate and delayed narrative recall, picture descriptions, and free responses. Key metrics including lexical and syntactic complexity, lexical frequency and diversity, and part of speech usage, both overall and post-pause, were examined.

Results: Significant differences in pause usage were observed between groups, with a higher incidence and longer latencies following these pauses in the MCI group. Lexical frequency following filled pauses was higher among MCI participants in the free response task but not in other tasks, potentially due to the relative cognitive load of the tasks. The immediate recall task was most useful at differentiating between groups. Predictive analyses utilizing random forest classifiers demonstrated high specificity in using speech behavior metrics to differentiate between MCI and HCs.

Conclusions: Speech behavior following pauses differs between MCI participants and healthy controls, with these differences being influenced by the cognitive demands of the speech tasks. These post-pause speech metrics can be easily integrated into existing speech analysis paradigms.

A conundrum in Alzheimer's disease (AD) is why the long-term use of acetylcholinesterase (AChE) inhibitors, intended for treatment of dementia, results in slowing neurodegeneration in the cholinergic basal forebrain, hippocampus, and cortex. The phospho-tau cascade hypothesis presented here attempts to answer that question by unifying three hallmark features of AD into a specific sequence of events. It is proposed that the hyperphosphorylation of tau protein leads to the AD-associated deficit of nerve growth factor (NGF), then to atrophy of the cholinergic basal forebrain and dementia. Because the release of pro-nerve growth factor (pro-NGF) is activity-dependent and is controlled by basal forebrain projections to the hippocampus and cortex, our hypothesis is that AChE inhibitors act by increasing acetylcholine-dependent pro-NGF release and, thus, augmenting the availability of mature NGF and improving basal forebrain survival. If correct, improved central nervous system-selective AChE inhibitor therapy started prophylactically, before AD-associated basal forebrain atrophy and cognitive impairment onset, has the potential to delay not only the onset of dementia but also its rate of advancement. The phospho-tau hypothesis thus suggests that preventing hyperphosphorylation of tau protein, early should be a high priority as a strategy to help reduce dementia and its associated widespread social and economic suffering.

MRI-visible enlarged perivascular spaces (EPVS) are common in patients with cognitive impairment and possibly linked to Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In a study of memory clinic patients (n = 450; mean age 66.5 ± 7.45, 45.8% female), we investigated CSF amyloid-β (Aβ)_1-42 (AD biomarker) and strictly lobar microbleeds (CAA marker) in relation to centrum semiovale EPVS (CSO-EPVS). Age-controlled analyses showed that severe CSO-EPVS associated with Aβ status (odds ratio [OR] = 1.51, 95%CI = 1.02-2.24), but not strictly lobar microbleeds (OR = 1.39, 95%CI = 0.92-2.11), with no significant Aβ status and microbleeds interaction. This implies that in this setting, severe CSO-EPVS is not a specific indicator of CAA.

Background: Tau accumulation in the nucleus basalis of Meynert (nbM) has been documented in Alzheimer's disease (AD), but its relationship to neuropathological changes in other brain regions and cognitive deficits remains unclear, particularly between early-onset AD (EOAD) and late-onset AD (LOAD).

Objective: To evaluate tau accumulation patterns in the nbM and other brain regions in EOAD and LOAD using ¹⁸F-florzolotau PET and examine correlations with cognitive function.

Methods: Thirty-eight amyloid-positive AD patients (15 EOAD, 23 LOAD) and 46 healthy controls underwent ¹⁸F-florzolotau PET. Tau levels were quantified in the nbM and Braak-staging regions. Postmortem brain samples were examined to assess ¹⁸F-florzolotau binding to tau deposits.

Results: EOAD showed a higher overall tau burden, including in the nbM, compared with LOAD. However, nbM tau levels correlated more strongly with cognitive decline in LOAD than EOAD. The relationship between nbM tau and neocortical tau differed between EOAD and LOAD. Histopathology revealed abundant ¹⁸F-florzolotau labeling of neurofibrillary tangles (NFTs) and ghost tangles in AD nbM samples.

Conclusions: This study provides the first in vivo PET evidence of differential nbM tau pathology between EOAD and LOAD, with higher accumulation but weaker correlation to cognition in EOAD. The distinct relationships between nbM and cortical tau in EOAD and LOAD suggest divergent pathological trajectories. ¹⁸F-florzolotau PET successfully visualized NFTs and extracellular ghost tangles in the nbM across AD stages. These findings highlight the importance of considering age of onset when evaluating tau pathology and its clinical correlates in AD.

Background: We have previously shown that droplet degeneration (DD) signifies the beginning of neuritic plaque formation during Alzheimer's disease (AD) pathogenesis. As microglia associated with neuritic plaques exhibited strong ferritin expression and Perl's iron staining showed iron in microglia, droplet spheres and neuritic plaque cores, we hypothesized that DD is a form of ferroptosis.

Objective: Detection of molecular markers of ferroptosis in AD brains.

Methods: Immunohistochemical detection of transferrin receptor (TfR) and ferritin as ferroptosis markers in prefrontal cortex of AD brains, investigation of spatial correlation of these with histopathological hallmarks of AD, visualization of ferroptotic marker genes by in situ hybridization, comparison of expression of ferroptosis genes with snRNAseq analyses and comparison of TfR and ferritin expression in different neurofibrillary tangle (NFT) stages.

Results: TfR was found on neurons that appeared to be degenerating and exhibited typical features of droplet degeneration. Co-localization with hyperphosphorylated tau (p-tau) was a rare event. TfR-positive neurons increased with higher NFT stages as did ferritin expression in microglia. mRNA of genes linked to ferroptosis was detected in pretangles and p-tau negative neurons, less in DD. snRNAseq analyses support a link between AD, ferroptosis and TfR as a ferroptosis marker.

Conclusions: Increased expression of TfR and ferritin in high NFT stages, demonstration of ferroptotic marker genes in Alzheimer's lesions, as well as snRNAseq analyses strengthen our hypothesis that DD represents ferroptosis. Because of the morphological similarity between TfR-positive structures and DD, TfR might be an early ferroptosis marker expressed transiently during AD pathogenesis.

Background: The association between cognitive neurodegenerative disease and oral diseases has been under great interest recently. Several studies have suggested a connection between periodontitis and Alzheimer's disease (AD) or other neurodegenerative disorders.

Objective: This study aimed to review the potential mechanisms between oral diseases and neurodegenerative diseases.

Methods: The study was executed as a literature review of English-language publications from 2018-2022. The databases used for the search were PubMed, Cochrane, Scopus, and Web of Science. The search phrases used were "neurodegenerative diseases" AND "oral health" and "neurodegenerative diseases" AND "oral diseases."

Results: The linkage between the two disease groups was observed in several distinct publications and several potential mechanisms were found. The link between periodontitis and AD proved to be the most significant. The effect was accentuated in elderly people where individuals possessed also other risk factors for neurodegenerative diseases and had generally worse oral health conditions.

Conclusions: Oral diseases may be risks for neurodegenerative changes along many different pathways. Good oral health should be acknowledged as a potential preventative or risk-reducing act against neurodegenerative diseases.

In the current scenario, Alzheimer's disease is a complex, challenging, and arduous health issue, and its prevalence, together with comorbidities, is accelerating around the universe. Alzheimer's disease is becoming a primary concern that significantly impacts an individual's status in life. The traditional treatment of Alzheimer's disease includes some synthetic drugs, which have numerous dangerous side effects, a high risk of recurrence, lower bioavailability, and limited treatment. Hence, the current article is a detailed study and review of all known information on plant-derived compounds as natural anti-Alzheimer's agents, including their biological sources, active phytochemical ingredients, and a possible mode of action. With the help of a scientific data search engine, including the National Center for Biotechnology Information (NCBI/PubMed), Science Direct, and Google Scholar, analysis from 2001 to 2024 has been completed. This article also described clinical studies on phytoconstituents used to treat Alzheimer's disease. Plant-derived compounds offer promising alternatives to synthetic drugs in treating Alzheimer's disease, with the potential for improving cognitive function and slowing down the progression of the disease. Further research and clinical trials are needed to fully explore their therapeutic potential and develop effective strategies for managing this complex condition.

Background: Alzheimer's disease (AD) is characterized by neurodegeneration linked to amyloid-β (Aβ) plaques and tau protein tangles. Protein kinase C alpha (PKCα) plays a crucial role in modulating amyloid-β protein precursor (AβPP) processing, potentially mitigating AD progression. Consequently, PKCα stands out as a promising target for AD therapy.

Objective: Despite the identification of numerous inhibitors, the pursuit of more effective and precisely targeted PKCα inhibitors remains crucial.

Methods: In this study, we employed an integrated virtual screening approach of molecular docking and molecular dynamics (MD) simulations to identify phytochemical inhibitors of PKCα from the IMPPAT database.

Results: Molecular docking screening via InstaDock identified compounds with strong binding affinities to PKCα. Subsequent ADMET and PASS analyses filtered out compounds with favorable pharmacokinetic profiles. Interaction analysis using Discovery Studio Visualizer and PyMOL further elucidated binding conformations of selected compounds with PKCα. Top hits underwent 200 ns MD simulations using GROMACS to validate stability of the interactions. Finally, we propose two phytochemicals, Kammogenin and Imperialine, with appreciable drug-likeliness and binding potential with PKCα.

Conclusions: Taken together, the findings suggest Kammogenin and Imperialine as potential PKCα inhibitors, highlighting their therapeutic promise for AD after further validation.