Journal of Alzheimer's Disease最新文献

Background: Insulin-like growth factor-1 (IGF-1) promotes neurogenesis, cell survival, and glial function, making it a promising candidate therapy in Alzheimer's disease (AD).

Objective: Long arginine 3-IGF-1 (LR3-IGF-1) is a potent IGF-1 analogue. We sought to determine whether intranasal (IN) LR3 treatment would delay cognitive decline and pathology in 5XFAD mice.

Methods: Wildtype and 5XFAD male mice were treated for 7 months (3-10 months of age), with IN LR3-IGF-1 or IN Vehicle (Veh) (n = 19-27 mice/group). Behavior, memory, and brain imaging were assessed at 8-9 months of age and tissues collected at 10 months. A comprehensive amyloid-β (Aβ) profile and other pathologic features were conducted and supportive in vitro stimulation studies in BV-2 microglial cells were also performed.

Results: In male 5XFAD mice, IN LR3-IGF-1 treatment improved body composition, but did not significantly alter cognitive symptoms, as assessed by multiple assays. In cortex, LR3 treatment improved some facets of pathology, including a reduction in filamentous plaques, and increase in inert plaques, corresponding with a reduction in low molecular weight Aβ oligomers. In vitro, uptake of Aβ_1-42 peptide by BV2 cells was enhanced by LR3-IGF-1, which was also found to promote gene pathways implicated in actin remodeling and endocytosis.

Conclusions: LR3 promotes favorable effects on Aβ plaque remodeling in cortex of male 5XFAD mice but fails to preserve aspects of behavior or memory. While these data do not support LR3 as a monotherapy per se, they do warrant further investigation into its potential for combinatorial formulations aimed at targeting the complexity of AD.

Background: Apathy in patients with Alzheimer's disease (AD) is associated with significant morbidity and is often one of the first neuropsychiatric symptoms to present in mild cognitive impairment (MCI). Apathy is associated with accelerated cognitive decline and atrophy in fronto-striatal regions of the brain. Previous work has shown a link between apathy and the APOE gene in the context of AD, as the APOE ε4 allele is already known to be associated with the onset of AD. However, other genetic associations with apathy are largely unexplored.

Objective: To examine whether interactions between genetic variants related to neurotransmitter systems and regional brain atrophy are associated with apathy in patients with MCI and AD.

Methods: In a sample of individuals with AD (n = 266), MCI (n = 518), and cognitively normal controls (n = 378), a partial least squares correspondence analysis modeled interactions between single nucleotide polymorphisms, structural whole-brain imaging variables, and apathy.

Results: An interaction was found between apathy, the possession of an APOE ε4 allele combined with minor homozygosity for the DAT1 (dopamine transporter 1) gene, and regional brain atrophy. This interaction was closely linked to the MCI and AD groups.

Conclusions: The results point to an association of a dopaminergic genetic marker and apathy in the AD continuum and may inform future design of clinical trials of apathy, as well as new treatment targets.

Background: The age distribution and diversity of the VA Million Veteran Program (MVP) cohort make it a valuable resource for studying the genetics of Alzheimer's disease (AD) and related dementias (ADRD).

Objective: We present and evaluate the performance of several International Classification of Diseases (ICD) code-based classification algorithms for AD, ADRD, and dementia for use in MVP genetic studies and other studies using VA electronic medical record (EMR) data. These were benchmarked relative to existing ICD algorithms and AD-medication-identified cases.

Methods: We used chart review of n = 103 MVP participants to evaluate diagnostic utility of the algorithms. Suitability for genetic studies was examined by assessing association with APOE ε4, the strongest genetic AD risk factor, in a large MVP cohort (n = 286 K).

Results: The newly developed MVP-ADRD algorithm performed well, comparable to the existing PheCode dementia algorithm (Phe-Dementia) in terms of sensitivity (0.95 and 0.95) and specificity (0.65 and 0.70). The strongest APOE ε4 associations were observed in cases identified using MVP-ADRD and Phe-Dementia augmented with medication-identified cases (MVP-ADRD or medication, p = 3.6 ×10^-290; Phe-Dementia or medication, p = 1.4 ×10^-290). Performance was improved when cases were restricted to those with onset age ≥60.

Conclusions: We found that our MVP-developed ICD-based algorithms had good performance in chart review and generated strong genetic signals, especially after inclusion of medication-identified cases. Ultimately, our MVP-derived algorithms are likely to have good performance in the broader VA, and their performance may also be suitable for use in other large-scale EMR-based biobanks in the absence of definitive biomarkers such as amyloid-PET and cerebrospinal fluid biomarkers.

Background: Alzheimer's disease (AD) is a neurodegenerative disease. At present, there are currently no drugs that can cure AD.

Objective: A number of empirical studies have shown that transcranial direct current stimulation (tDCS) may be used to treat cognitive abnormalities in patients with AD. We will through meta-analysis reviews tDCS overall research on the effects of cognitive function in patients with AD.

Methods: Systematic searches were performed in the PubMed, Embase, and Cochrane Library databases from their creation until 8 March 2024. Using a fixed effect model and random effect model to evaluate the average difference between the treatment group and control group (MD) and its 95% confidence interval (CI).

Results: The study included 10 randomized controlled trials (Nactive = 165, Nsham = 167). The results of the overall analysis showed that tDCS did not significantly improve the overall cognitive function (SMD = 0.17; 95%CI = -0.05, 0.39; p = 0.14; I² = 51%). Quality of life of AD patients after treatment was also evaluated, but no improvement was seen. Subgroup analysis showed no significant improvement in global cognitive function after tDCS treatment. The sensitivity analysis to confirm the reliability of the data, risk assessment did not find any high-risk projects.

Conclusions: The tDCS treatment did not improve cognitive function in patients with AD. Further empirical research in the future will help to explore new schemes for tDCS to improve cognitive function of patients.

Background: Obstructive sleep apnea (OSA) is highly prevalent among older adults and has been associated with cognitive decline and dementia risk. The suitability of screening tools for detecting OSA in memory clinic settings is unclear.

Objective: To evaluate the utility and validity of the STOP-Bang questionnaire (SBQ) and pulse oximeter as a screening tool, compared to gold-standard polysomnography (PSG) in older adults attending a memory clinic.

Methods: Participants aged over 50 with new onset cognitive/mood concerns attended a memory clinic, then completed the SBQ, oximetry, and PSG. The SBQ and oximetry's accuracy in detecting moderate-severe and severe OSA was evaluated using receiver operating curves. Intraclass correlation and Bland-Altman plots compared the oximeter's adjusted oxygen desaturation index (ODI-Ox) and PSG's apnea-hypopnea index (AHI-PSG).

Results: Of 194 participants (mean age = 65.6, 64 males) who completed PSG, 184 completed the SBQ, and 138 completed oximetry. SBQ demonstrated limited performance for moderate-severe OSA (sensitivity = 52%, specificity = 62%, AUC = 0.600) and severe OSA (sensitivity = 18%, specificity = 87%, AUC = 0.577). Oximetry was satisfactory for moderate-severe OSA (sensitivity = 67%, specificity = 73%, AUC = 0.769) and severe OSA (sensitivity = 50%, specificity = 88%, AUC = 0.730). The diagnostic performance was improved with new cut-offs at ODI-Ox ≥ 11 for AHI-PSG ≥ 15 and ODI-Ox ≥ 20 for AHI-PSG ≥ 30. Bland-Altman plots and intraclass correlation indicated acceptable agreement for oximetry.

Conclusions: The findings suggest that while the SBQ may be unsuitable to detect moderate or severe OSA for older adults with cognitive impairment, oximetry may be a viable screening tool. Given OSA treatment can optimize sleep and may slow cognitive decline, routine screening for OSA should be part of memory clinic assessments.

Background: Alzheimer's disease (AD) is the most common neurodegenerative dementia, with diagnosis traditionally reliant on clinical criteria. Cerebrospinal fluid (CSF) biomarkers like pTau181 and Aβ₄₂/Aβ₄₀ ratio significantly improve diagnostic accuracy but are invasive. Plasma biomarkers measured by automated assays offer a non-invasive alternative.

Objective: To evaluate the diagnostic performance of plasma pTau181, Aβ₄₂/Aβ₄₀, and pTau181/Aβ₄₂ ratios in predicting CSF amyloid status in a real-life clinical setting.

Methods: Data from consecutive patients whose plasma and CSF samples sent to our laboratory between March and October 2022, were retrospectively analyzed. Plasma and CSF pTau181, Aβ₄₂, and Aβ₄₀ levels were measured using the Lumipulse G600II platform. CSF amyloid status was classified as amyloid-positive (A+) or amyloid-negative (A-) based on the Aβ₄₂/Aβ₄₀ ratio. Statistical analyses included Spearman correlation, receiver operating characteristic (ROC) curves, and multivariate logistic regression to evaluate biomarker performance.

Results: Among 165 individuals (83 females), 29.1% were classified as A+. Significant correlations were found between plasma and CSF biomarkers, with the highest for the pTau181/Aβ₄₂ ratio (ρ=0.620, p < 0.0001). ROC analysis showed the pTau181/Aβ₄₂ ratio had the highest diagnostic performance (AUC 0.818), followed by pTau181 (AUC 0.794) and Aβ₄₂/Aβ₄₀ (AUC 0.775). Combining plasma biomarkers in age-adjusted models improved diagnostic accuracy (AUC up to 0.846).

Conclusions: Plasma biomarkers measured by the Lumipulse G600II platform show strong potential in predicting CSF amyloid status and possibly reduces the need for lumbar punctures. These findings support the potential use of plasma assays in the early diagnosis of AD. Anyway, further validations in larger multicenter cohorts are mandatory.

The prevalence and global health burden of dementia including Alzheimer's disease (AD) is rising, while patients living in remote and underserved areas face significant challenges in reaching specialized care. Telemedicine offers a valuable solution in bridging this widening gap, by providing equal and timely access to tertiary-specialized centers. Accumulating evidence highlights that most parts of the remote neuropsychological and neurological evaluation are feasible, with patients, healthcare professionals and caregivers being generally satisfied with this means of care. Herein, we provide an updated overview of the available evidence on the use of telemedicine for patients with cognitive disorders, focusing on the different applications and settings, the remote, video-based neurological and neuropsychological assessment, current recommendations, non-pharmacological interventions, as well as legal and ethical considerations. Based on the literature review and our three-year experience in the "Specialized Outpatient Clinic of Memory, Dementia and Parkinson's disease through the National Telemedicine Network" in the Aiginition University Hospital of Athens, we propose a brief guide for assessing patients with cognitive impairment via telemedicine and suggest future research directions for the more effective and appropriate use of telemedicine in dementia assessment and care.

Several studies indicate that the development of Alzheimer's disease (AD) has strong interactions with immune mechanisms within the brain, indicating a close association between inflammation in the central nervous system and the progression of neurodegeneration. Despite considerable progress in understanding the inflammatory aspects of AD, several of them remain unresolved. Pro-inflammatory cytokines and microglia are pivotal components in the inflammatory cascade. Among these, the role of interleukin-8 (IL-8) in neurodegeneration seems complex and multifaceted, involving inflammation, neurotoxicity, blood-brain barrier disruption, and oxidative stress, and is still poorly characterized. We conducted a review to describe the evidence of IL-8 involvement in AD. IL-8 is a cytokine known for its proinflammatory properties and typically produced by macrophages, predominantly functions as a chemotactic signal for attracting neutrophils to inflamed sites in the bloodstream. Interestingly, IL-8 is also present in the brain, where it is primarily released by microglia in response to inflammatory signals. This review aims to provide a comprehensive overview of the structure, function, and regulatory mechanisms of IL-8 relevant to AD pathology.

Background: Depression in old age is associated with the incidence of dementia. However, whether a combination of somatic and psychological symptoms influences the risk of dementia has not been fully investigated.

Objective: We aimed to determine the association between the combination of psychological and somatic symptoms of depression and the incidence of dementia.

Methods: This prospective cohort study included 2111 community-dwelling older adults (median age = 73 years, interquartile range = 68-78 years, 39.5% male). Participants were evaluated for 5 years from baseline to assess the incidence of dementia. Somatic symptoms were defined as the presence of one or more symptoms of fatigue, weight loss, sleep disturbances, and abnormal appetite. Psychological symptoms were assessed using the 15-item Geriatric Depression Scale. Participants were stratified into four groups based on the presence or absence of somatic and psychological symptoms. A Cox proportional hazards model was used to examine the associations with the incidence of dementia, adjusted for potential confounders.

Results: The hazard ratios for the incidence of dementia in the somatic (HR 1.42, 95% CI: 0.96-2.09) and psychological symptoms-only groups (HR 1.47, 95% CI: 0.83-2.59) were not significantly different; however, they were significantly higher in the coexistent group than in the normal group (HR 1.91, 95% CI: 1.24-2.94).

Conclusions: The coexistence of somatic and psychological symptoms of depression increases the risk of dementia. Therefore, interventions should consider both somatic and psychological symptoms to prevent or delay dementia.

Background: Quantitative susceptibility mapping (QSM) is pivotal for analyzing neurodegenerative diseases. However, accurate hippocampal segmentation remains a challenge.

Objective: This study introduces a method for extracting hippocampal magnetic susceptibility values using a convolutional neural network (CNN) model referred to as 3D residual UNET.

Methods: The model was pre-trained on whole QSM images and hippocampal segmentations from 3D T1-weighted images of 297 patients with Alzheimer's disease and mild cognitive impairment. Fine-tuning was conducted through manually annotated hippocampal segmentations from the QSM images of 60 patients. The performance was assessed using the Dice similarity coefficient (DSC) and Pearson correlation coefficient.

Results: The developed model was applied to another 98 patients, 49 with AD and 49 with mild cognitive impairment (MCI), and the correlation between the hippocampal magnetic susceptibility and volume was evaluated. The mean DSC for the hippocampal segmentation model was 0.716 ± 0.045. The correlation coefficient between the magnetic susceptibility values derived from manual segmentation and the CNN model was 0.983. The Pearson correlation coefficient between magnetic susceptibility and hippocampal volume from the CNN model was -0.252 (p = 0.012) on the left side and -0.311 (p = 0.002) on the right.

Conclusions: The 3D residual UNET model enhances hippocampal analysis precision using QSM, which is capable of accurately extracting magnetic susceptibility.