Alzheimer's Research & Therapy最新文献

Background: Vascular damage, including cerebral amyloid angiopathy (CAA) and non-amyloid cerebral small vessel disease (CSVD), has been linked to glymphatic dysfunction, which may contribute to Alzheimer's disease (AD) pathology and cognitive decline. We investigated the associations among vascular damage, glymphatic function measured by the DTI-ALPS (Diffusion Tensor Imaging-Analysis Along the Perivascular Space) index, AD plasma biomarkers, and cognitive decline.

Methods: This study includes 1,249 participants recruited from Samsung Medical Center. We performed linear regression analysis to identify factors associated with the DTI-ALPS index. Further, linear regression analysis with vascular imaging markers, including CAA and CSVD summary scores, as predictors and DTI-ALPS index as an outcome was performed to investigate the effect of vascular pathology on glymphatic function. We conducted mediation analyses to investigate whether the DTI-ALPS index mediates the effect of vascular imaging markers on plasma biomarkers (phosphorylated tau 217 [p-tau 217], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NFL]). Additionally, mediation analyses with the DTI-ALPS index as a predictor, each plasma biomarker as a mediator, and annual MMSE or CDR-SOB change as an outcome to investigate whether plasma biomarkers mediate the effect of the DTI-ALPS index on longitudinal cognitive decline.

Results: First, the DTI-ALPS index was negatively associated with both CAA (β [95% CI] = -0.163 [-0.214, -0.112], p < 0.0001) and CSVD (β [95% CI] = -0.195 [-0.247, -0.143], p < 0.0001) summary scores after controlling for age, sex, BMI status, and APOE genotype. Second, the DTI-ALPS index fully mediated the relationship between these vascular markers and p-tau 217 (CSVD summary score, indirect effect β [95% CI] = 0.016 [0.010, 0.023], p < 0.001; CAA summary score, indirect effect β [95% CI] = 0.013 [0.008, 0.020], p < 0.001) and GFAP (CSVD summary score, indirect effect β [95% CI] = 0.015 [0.008, 0.022], p < 0.001; CAA summary score, indirect effect β [95% CI] = 0.012 [0.007, 0.019], p < 0.001), while partially mediating the relationship for NFL, regardless of Aβ uptake on PET. Finally, the DTI-ALPS index was significantly associated with cognitive decline and this association was partially mediated by plasma biomarkers.

Conclusions: These findings highlight glymphatic dysfunction as a key mechanism linking vascular pathology with tau, inflammation and neurodegeneration, independent of Aβ uptakes.

Cerebrovascular dysfunction (CVD) is increasingly recognized as a contributor to Alzheimer's disease (AD) progression. Adiponectin (APN), an adipocyte-derived hormone with vasoprotective properties in the periphery, has an unclear impact on AD-related cerebrovascular integrity. We showed that APN-deficient mice exhibited reduced resting cerebral blood flow (CBF), impaired neurovascular coupling (NVC), disrupted blood-brain barrier (BBB), and enhanced cerebral amyloid angiopathy (CAA), which are CVD characteristics that also observed in 5xFAD mice, a model of AD. Notably, APN-deficient 5xFAD mice displayed more severe CVD than 5xFAD mice alone. Transcriptomic analysis of brain endothelial cells (ECs) identified dysregulated biological processes and key signaling pathways underlying EC dysfunction. Importantly, the administration of APN restored CBF and NVC in 5xFAD mice, and prevented tight junction protein (TJP) loss and barrier breakdown in Aβ40-exposed primary ECs. These results highlight the potential of alleviating CVD through targeting ECs with APN as a promising therapeutic strategy to delay the onset and mitigate the progression of AD.

Background: To evaluate retinal structural and vascular differences in probable Alzheimer's disease (AD) and mild cognitive impairment (MCI) using optical coherence tomography (OCT) and OCT angiography (OCTA), and to assess their combined performance in differentiating MCI/probable AD individuals with no cognitive impairment (NCI).

Methods: A cross-sectional study of 196 participants (NCI = 60; MCI = 83; probable AD = 53) recruited from two memory clinics, with good-quality OCT and OCTA scans, was conducted. Retinal layer thickness and vessel density were calculated using OCT/OCTA. Generalized estimating equations were used to compare groups, adjusting for relevant covariates. Receiver operating characteristic (ROC) curves assessed diagnostic accuracy.

Results: Participants with MCI/probable AD were older (77 ± 6 years vs. 73 ± 9 years, p = 0.004) compared with controls, but sex distribution was similar (40% vs. 42% male, p = 0.796). The inner nuclear layer (β = 1.70 μm, p = 0.028) and inner segment/outer segment (IS/OS) layers (β = 0.51 μm, p = 0.003) were significantly thicker, while the outer nuclear layer was significantly thinner (β=-5.80 μm, p = 0.049) in MCI/probable AD participants compared to normal controls. OCTA showed reduced vessel densities in the superficial (β=-0.69%, p = 0.018) and deep capillary plexuses (β=-2.23%, p = 0.010), along with a larger deep foveal avascular zone perimeter (β = 0.18 μm, p = 0.038) in MCI/AD. Diagnostic performance was moderate for individual OCT (0.52-0.64) and OCTA layers (0.56-0.66). Combining OCT and OCTA significantly improved diagnostic accuracy (AUC = 0.90, p < 0.001), with a sensitivity of 81%, specificity of 87%, and highest Youden Index (0.67), compared to OCTA (0.55) and OCT (0.47).

Conclusions: Integrating OCT- and OCTA-derived metrics significantly improved discriminative performance compared with either modality alone, underscoring their complementary value in capturing distinct structural and vascular alterations associated with cognitive impairment.

Background: Lacunar infarction (LI), a subtype of ischemic stroke caused by cerebral small vessel disease (SVD), is strongly associated with post-stroke cognitive impairment (PSCI). While neuroimaging biomarkers are critical for diagnosis, their accessibility and cost limit routine use. The retina, as an extension of the central nervous system, offers a non-invasive window to study microvascular pathology. This study investigates the synergistic impact of infarct lesion volume and retinal microvascular metrics on cognitive impairment in LI patients.

Methods: We prospectively enrolled 112 LI patients and 128 controls. Retinal vascular parameters (tortuosity, vessel density, fractal dimension) were quantified from color fundus photographs, and lesion diameter was measured via MRI. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Linear regression models with generalized estimating equations (GEE) evaluated associations between retinal metrics, lesion diameter, and MoCA scores, adjusting for covariates (age, vascular risk factors). Interaction terms tested the moderating effects.

Results: LI patients exhibited sparser, more tortuous retinal microvasculature compared to controls (p < 0.001). Poorer cognitive performance in LI was associated with larger lesion diameter (p < 0.001) and retinal microvascular impairment. A significant interaction was observed between retinal microvasculature and lesion diameter on MoCA scores (fractal dimension: ß = 1.532, p for interaction = 0.026; vessel density: ß = 0.53, p for interaction = 0.041), suggesting that the relationship between lesion diameter and MoCA scores may be more pronounced in LI with severe retinal microvascular impairment.

Conclusions: The diameter of the lesion infarct and severity of retinal microvascular damage may jointly reflect global cognitive performance in LI, signifying ischemia as a potential shared mechanism. Integrating retinal imaging with neuroimaging may enhance early risk stratification and personalized intervention strategies.

Background: Sleep is essential for brain homeostasis, in part by supporting glymphatic clearance through sleep-related oscillations. However, the relationship between putative glymphatic metrics and coupled sleep rhythm disruption, and their combined role in Alzheimer's disease (AD) progression, remains poorly understood.

Methods: We analyzed data from 75 individuals, 54 with AD and 21 cognitively normal (CN) controls, including sleep electroencephalography (EEG), magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) AD biomarkers, and two-year longitudinal cognitive assessments. Putative glymphatic metrics was evaluated using choroid plexus (CP) volume, perivascular spaces (PVSs), diffusion tensor imaging along the perivascular space (DTI-ALPS) index, and blood oxygen level-dependent signal coupled to CSF signal (BOLD-CSF coupling). Coupled sleep rhythm was assessed via slow oscillation (SO)-theta and SO-spindle couplings. Correlation and mediation analyses explored associations between these MRI-derived indices and coupled sleep oscillations, and least absolute shrinkage and selection operator (LASSO) regression was used to predict AD progression.

Results: Compared to CN controls, individuals with AD had reduced DTI-ALPS index and BOLD-CSF coupling (p < 0.05), along with disrupted SO-spindle coupling (p = 0.029). Across all participants, lower global BOLD-CSF coupling correlated with misaligned SO-theta burst coupling (r = 0.311, p = 0.018), and reduced DTI-ALPS was associated with misaligned SO-spindle coupling (r = 0.370, p = 0.008). In the AD group, DTI-ALPS remained correlated with SO-spindle misalignment (r = 0.376, p = 0.028). Mediation analysis revealed that SO-spindle misalignment contributed to cognitive decline through its effect on DTI-ALPS. Importantly, combining putative glymphatic and sleep EEG metrics effectively predicted AD progression.

Conclusions: Our findings suggest that disruptions in surrogates marker of glymphatic clearance and coupled sleep rhythms are jointly associated with AD-related cognitive decline. These metrics offer a promising framework for predicting disease progression and understanding neurodegenerative mechanisms in AD.

Background: Alzheimer's disease (AD) and dementia pose a significant clinical and economic burden globally. Early diagnosis and intervention can potentially delay disease progression. Current diagnostic guidelines recommend considering imaging and biomarker analysis in conjunction with clinical evaluation. Given limited healthcare resources, evidence on the cost-effectiveness of diagnostic technologies is critical to guide allocation of resources.

Objective: To systematically review the economic evaluation studies of neuroimaging, biomarkers, and other diagnostic or screening strategies for diagnosing and/or tracking the progression of AD or dementia.

Methods: A comprehensive search was conducted across Medline, Embase, PsycINFO, CINAHL and EconLit, and to identify relevant studies, with no restrictions on country, language, or publication period. Quality of the studies was evaluated using the Consensus on Health Economic Criteria-Extended (CHEC-Extended) checklist.

Results: Out of 6,804 records, 21 studies met the eligibility criteria. These included evaluations of neuroimaging technologies such as Positron Emission Tomography, Single Photon Emission Computed Tomography, Computed Tomography, and Magnetic Resonance Imaging (n = 10), cerebrospinal fluid and blood biomarkers (n = 7), and alternative diagnostic strategies including screening programs, machine learning-based models, and multidisciplinary care approaches (n = 4). Among the studies evaluating imaging technologies, most (n = 6) did not find them to be cost-effective. In contrast, CSF and blood biomarker studies found these technologies to be cost-effective, with some variability in results. Methodological quality score ranged between 15% and 95%, indicating a mix of low- to high-quality studies. Due to heterogeneity in study designs and reported outcomes, direct comparisons were not feasible.

Conclusions: While many studies were of high quality, heterogeneity in study objectives, design, and outcomes restricted evidence synthesis. Future research should ensure methodological consistency, transparent cost reporting, and integration of new treatment frameworks to improve the policy relevance and reliability of economic evidence for AD diagnostics.