Alzheimer's Research & Therapy最新文献

Background: We aimed to develop individualized predictions for risk of developing any-cause dementia and Alzheimer's disease (AD) dementia, in individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI), using plasma phosphorylated-tau-181 (pTau181), phosphorylated-tau-217 (pTau217; in a subset), amyloid beta1-42/1-40 (Aβ42/40), glial fibrillary acidic protein (GFAP) and/or neurofilament light (NfL).

Methods: From the Amsterdam Dementia Cohort we included 314 individuals with SCD (age 61 ± 9 years, n = 184 (59%) male, MMSE 29 ± 1) and 253 individuals with MCI (age 65 ± 7 years, n = 165 (65%) male, MMSE 27 ± 2), who had annual follow-up (median duration 2.4 years). Cox proportional hazards regression models were used to calculate probabilities for progression to dementia and were externally validated in MEMENTO and AIBL cohorts.

Results: During follow-up 20 SCD and 99 MCI patients developed dementia. For MCI patients who progressed to any form of dementia, plasma GFAP contributed on top of age, sex, and MMSE score in the parsimonious individualized prognostic model (C-index = 0.69 [95%CI = 0.63; 0.76]). With AD-dementia as the outcome, GFAP and pTau181 were selected in the parsimonious model on top of the demographic variables (C-index = 0.71 [95%CI = 0.65; 0.76]). In the subset of 197 MCI individuals with pTau217 measurements, pTau217 was selected in the parsimonious model on top of the demographic variables (C-index = 0.75 [95%CI = 0.69; 0.79]). External validation demonstrated that the models are robust in a memory clinic setting.

Conclusions: Our prediction models have utility for clinical practice to calculate progression probabilities for development of dementia in individual patients living with MCI over a 1-, 3- and 5-year time period.

Background: Primary central nervous system lymphoma (PCNSL) often manifests with cognitive impairment or nonspecific symptoms, which can delay diagnosis and worsen prognosis. However, the mechanisms underlying these neurological manifestations remain poorly understood. Previous studies have shown that polyglutamylation, a posttranslational modification, is associated with better responses to methotrexate-based chemotherapy in patients with PCNSL. Moreover, excessive polyglutamylation in neurons has been implicated in neurodegeneration via phosphorylated tau accumulation. This study aimed to elucidate the relationship between polyglutamylation, phosphorylated tau, and cognitive impairment in PCNSL.

Methods: We retrospectively analyzed 140 patients with histologically confirmed PCNSL treated at our institution between 2001 and 2022. Cognitive status at hospital admission was assessed using the Clinical Dementia Rating (CDR) scale. Immunohistochemical analysis of tumor specimens was performed to quantify the polyglutamylation and phosphorylated tau levels. Furthermore, in vitro studies with PCNSL cell lines were conducted to investigate whether the pharmacological upregulation of polyglutamylation by a histone deacetylase inhibitor promotes tau phosphorylation. Statistical analyses examined associations among polyglutamylation status, cognitive impairment, tau phosphorylation, and clinical outcomes.

Results: High polyglutamylation levels were observed in 59% of tumor samples, and this factor was independently associated with cognitive impairment at diagnosis (odds ratio: 3.83, 95% confidence interval 1.19-12.3, p = 0.024). Immunohistochemical analysis demonstrated that tumors with elevated polyglutamylation showed significantly higher phosphorylated tau levels. In vitro experiments confirmed that increased polyglutamylation levels in PCNSL cells led to enhanced tau phosphorylation in PCNSL cell lines.

Conclusions: High polyglutamylation levels in PCNSL were associated with cognitive impairment and increased tau phosphorylation at diagnosis. These findings suggest that polyglutamylation may contribute to neurocognitive symptoms by promoting tau pathology. Elucidating this mechanism may provide novel insights into PCNSL pathophysiology and may inform future studies on disease mechanisms and potential treatment targets.

Transcranial alternating current stimulation (tACS) in the theta frequency range has been shown to enhance working memory (WM) performance. However, no studies have directly compared the effects of theta tACS between cognitively healthy elderly (HE) subjects and subjects with non-amnestic mild cognitive impairment (MCI). Our proof-of-concept study investigated the effects of monofocal (frontal) and bifocal (frontoparietal) theta tACS on WM in two cognitive loads in HE subjects and in subjects with MCI. In this sham-controlled, single-blinded, repeated-measures study with counterbalanced stimulation order across subjects (n = 55), theta tACS (4.51 Hz, 1.5 mA, 20 min) was applied either over the frontal site alone or simultaneously over frontal and parietal sites. WM 2-back and 3-back tasks were performed during and after each stimulation session. In the HE group, both frontal and frontoparietal stimulations improved performance, albeit with load-dependent differences. Frontal stimulation was particularly effective in the higher cognitive load, enhancing accuracy (β = -3.87; p = .033) and reaction times (β = - .042; p = .002) in the 3-back task. Frontoparietal stimulation improved accuracy (β = -3.74; p = .027) but not reaction time (p > .22) in the 2-back task in the HE group. Frontoparietal stimulation enhanced accuracy in the 3-back task across all participants (β = 1.91; p = .043). In the MCI group, frontal stimulation led to faster reaction times in the 3-back task, although the effects were not robust. Lastly, a marginally significant improvement in reaction times was observed in a letter 2-back transfer task following frontal stimulation (β = - .034; p < .092) across all participants. Our findings indicate that theta tACS over the frontal and frontoparietal areas elicits benefits in WM performance, driven mainly by enhancements in HE subjects. The effects of stimulation varied with cognitive load and montage, suggesting that optimal stimulation parameters may differ depending on task demands. The non-amnestic MCI group did not exhibit greater improvements despite their lower baseline performance, possibly due to higher variability in pathology and compensation. Multiple sessions or alternative stimulation parameters may be needed to achieve robust effects in subjects with MCI. The study was retrospectively registered on ClinicalTrials.gov (NCT06563453).

Background: Mitochondrial dysfunction and dysregulated calcium homeostasis contribute to Alzheimer's disease (AD) pathogenesis. The extrasynaptic N-methyl-D-aspartic acid (NMDA) receptor (eNMDAR) plays a crucial role in calcium influx and subsequent signaling cascades. In individuals with AD, the reduced expression and function of glutamate transporter-1 (GLT-1) result in glutamate spillover from the synaptic clefts to the extrasynaptic region, thereby activating eNMDAR and inducing mitochondrial damage. Ceftriaxone (Cef) has been reported to ameliorate cognitive deficits in APPswe/PS1dE9 (APP/PS1) mice by upregulating GLT-1. This study aimed to explore whether Cef alleviates mitochondrial dysfunction to improve cognitive impairment and the roles of GLT-1 and eNMDAR, particularly the participation of eNMDAR-induced intracellular calcium signaling in this process.

Methods: C57BL/6J, APP/PS1, and GLT-1-knockdown APP/PS1 mice were used. NMDA (1 mM, 2 µL per ventricle) was injected cerebroventricularly into APP/PS1 mice once to activate eNMDAR. Cef (200 mg/kg) was intraperitoneally administered for 14 days. Cognitive function was evaluated by novel object recognition, novel location recognition and Morris water maze tests. Hippocampal mitochondrial ultrastructure was observed using transmission electron microscopy. Hippocampal mitochondrial membrane potential (MMP) was detected using JC-1 staining. The expression of eNMDAR and proteins related to mitochondrial biogenesis and dynamics was evaluated by western blot. A neuron‒astrocyte coculture derived from the cerebral cortex of embryonic mice was used to evaluate the effects of Cef on eNMDAR-induced neuronal calcium influx, mitochondrial calcium accumulation and MMP loss using live-cell imaging.

Results: Cef treatment attenuated hippocampal mitochondrial dysfunction, including ultrastructural damage, reduced aspect ratio, dysregulation of MMP, impaired biogenesis and dynamics, and cognitive deficits, and prevented the upregulation of eNMDAR expression in APP/PS1 mice in a GLT-1-dependent manner. These protective effects on hippocampal mitochondrial dysfunction and cognitive deficits were counteracted by eNMDAR activation. Furthermore, Cef incubation inhibited eNMDAR-mediated calcium influx in a GLT-1-dependent way and reduced MMP in primary cortical neurons. Notably, Cef incubation significantly suppressed mitochondrial calcium overload, which was mechanistically linked to the observed decline in MMP.

Conclusions: Cef treatment prevented the upregulation of eNMDAR expression and the subsequent extracellular calcium influx in a GLT-1-dependent manner, thereby reducing mitochondrial calcium loading and ultimately mitigating mitochondrial damage and cognitive deficits in APP/PS1 mice.

Background: More than 300 mutations in presenilin 1 (PSEN1) lead to autosomal dominant Alzheimer's disease (ADAD). PSEN1, as the catalytic subunit of γ-secretase, generates amyloid-β (Aβ) peptides through a sequential proteolysis of the amyloid precursor protein (APP). While ADAD typically presents with progressive cognitive decline, ~ 25% of PSEN1 mutation carriers develop spastic paraparesis (SP), a debilitating motor condition. The molecular basis of this phenotypic heterogeneity remains unknown. This study examines Aβ profiles generated by PSEN1 variants associated with different clinical presentations with the aim of exploring potential associations between different Aβ profiles and clinical heterogeneity.

Methods: We analysed reported Aβ peptide profiles generated in vitro by 160 PSEN1 variants, categorized by their associated AD or AD + SP phenotype. We employed an integrated analytical approach combining univariate comparisons of Aβ profiles with machine learning classification.

Results: AD + SP-linked mutations showed significantly higher Aβ43 levels and more severe impairments in γ-secretase processivity compared to pure dementia associated variants. Machine learning consistently identified Aβ43 as the most important feature allowing for the phenotypic classification. Unlike processivity impairments, total Aβ production was comparable between groups, suggesting specific rather than global alterations in γ-secretase function.

Conclusions: Our analysis reveals a robust association between elevated Aβ43 levels and SP development in PSEN1 mutation carriers. While this correlation does not establish causation, the distinct impact of SP-associated mutations on γ-secretase function, resulting in elevated Aβ43 production, suggests that mutation-specific mechanisms may underlie clinical heterogeneity in ADAD, with potential implications for biomarker and translational research.