Journal of Alzheimer's Disease最新文献

BackgroundMarkers of synaptic degeneration and neuroinflammation have been investigated in memory clinic cohorts, but less is known about their role in community-dwelling subjects.ObjectiveTo investigate baseline cerebrospinal fluid (CSF) levels of neurogranin and YKL-40 in community-dwelling subjects with mild cognitive impairment (MCI) who had not yet sought help for their cognitive decline.MethodsWe recruited and characterized 107 subjects, who at the clinical baseline examination were found to have MCI. Based on the clinical progression at a 3-year follow-up, the individuals were classified as MCI-Alzheimer's disease (MCI-AD, n = 40), MCI-vascular dementia (MCI-VaD, n = 25), and stable MCI (sMCI, n = 42).ResultsBaseline CSF neurogranin level was elevated in the MCI-AD group compared with the MCI-VaD and sMCI groups (p = 0.02 and p < 0.001, respectively), and baseline CSF YKL-40 level was higher in the MCI-AD group than in the sMCI group (p = 0.01). Neurogranin, and to a lesser extent YKL-40, correlated positively with CSF levels of total tau and phosphorylated tau₁₈₁ in all study groups. However, in receiver operator characteristics analyses, neurogranin and YKL-40 used alone or in combination had a moderate diagnostic accuracy that was lower than that of the core AD biomarkers (amyloid-β₄₂, total tau, and phosphorylated tau₁₈₁).ConclusionsThis study shows that neurogranin and YKL-40 in CSF are elevated in MCI-AD compared with sMCI, and neurogranin was also higher in MCI-AD than in MCI-VaD. Neurogranin and YKL-40 had a moderate diagnostic accuracy, but they could still be of value to characterize the clinical consequences of postsynaptic dysfunction and neuroinflammation.

BackgroundAlzheimer's disease (AD) patients experience elevated mortality during emergency department (ED) encounters, yet the associated risk factors remain insufficiently characterized.ObjectiveTo identify predictors of mortality among older adults with AD during ED visits and examine differences in comorbidity patterns between those who died and those who survived.MethodsWe analyzed 20,532,351 ED visits for adults aged ≥60 from the 2012-2014 Nationwide Emergency Department Sample (NEDS). Visits were stratified by AD status, ZIP-code income quartile, and mortality outcome (defined as in-ED or in-hospital death following ED presentation). We used logistic regression and machine learning models (random forest, gradient boosting, XGBoost) to predict mortality in a 1:1 matched case-control dataset. SHapley Additive exPlanations (SHAP) were applied to interpret model outputs.ResultsAD patients accounted for 1.76-2.13% of all ED visits, with mortality rates of 2.55-2.68% compared to 1.10-1.76% for non-AD patients. Socioeconomic status and ED charges were not associated with increased mortality. Odds ratio analysis identified rare terminal events as top predictors (e.g., respiratory arrest, OR = 55.5), while SHAP analysis highlighted more prevalent and clinically actionable conditions such as acute respiratory failure and septicemia as major drivers of mortality. All models performed comparably (AUC ≈ 0.85).ConclusionsAD patients face significantly higher mortality during ED encounters. Integrating explainable machine learning with large-scale administrative data may help flag lethal comorbidities in real time and improve outcomes through better ED triage and care prioritization.

Emerging evidence suggests that various microbes and mites may play a significant role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Lewy body dementia (LBD), and Parkinson's disease (PD). The association between microbial exposure and these conditions raises the possibility that mites, as vectors or direct agents, could contribute to disease onset and progression. PD, with 15% or less of cases linked to genetics, highlights the importance of environmental factors in the remaining sporadic cases. Mites, known to harbor prions, suggest a potential mechanism for horizontal transmission. Mites can inject neurotoxins that may disrupt neurological systems, potentially leading to movement disorders, memory loss, and cognitive decline. Conditions like seborrheic dermatitis and rosacea, linked to mites such as Demodex, are highly prevalent in patients with PD and AD, and mite-induced inflammation may exacerbate disease symptoms. Mite infestations can cause systemic illness, including respiratory, gastrointestinal, and neurological disturbances. Due to their microscopic size, they are often undetected and potentially can swap DNA with humans. This article summarizes observations linking mite exposure to neurodegenerative diseases. In one family, a member was diagnosed with LBD following chronic skin issues and mite exposure, while another developed symptoms associated with PD. Mites may contribute through prion transmission, neurotoxin injection, or by triggering inflammation. A nationwide study found that scabies patients treated with lindane, a neurotoxic pesticide, had a significantly reduced PD risk, suggesting a protective effect. These findings underscore the urgent need for further research into mites and environmental triggers.

BackgroundNeuropsychiatric signs and symptoms (NPS) are highly prevalent in Alzheimer's disease (AD), but whether co-occurring symptom constellations relate to regional amyloid deposition remains unclear.ObjectiveTo identify reproducible NPS clusters in AD and examine their associations with regional amyloid deposition using ¹⁸F-FC119S positron emission tomography (PET).MethodsWe included 143 patients with probable AD and positive amyloid PET. NPS were assessed with the Korean Neuropsychiatric Inventory, and hierarchical cluster analysis (Yule's Q, average linkage) identified symptom clusters. Regional amyloid burden in frontal, temporal, and parietal cortices was quantified by automated SUVRs. Clinical characteristics were compared using t tests, and associations between clusters and regional amyloid patterns were examined with Pearson's χ².ResultsFour clusters emerged: Group 1 (delusion, agitation-aggression, disinhibition, aberrant motor behavior); Group 2 (depression, anxiety, irritability); Group 3 (hallucination, euphoria, nighttime behavior, apathy); and Group 4 (eating abnormalities). Group 1 patients were older with worse global status (lower K-MMSE, higher CDR, lower Barthel); Group 2 showed higher GDS15 scores; Group 3 showed selectively lower K-MMSE; Group 4 showed no significant differences. On PET, Group 1 was associated with right frontal and right temporal positivity; Group 2 with left parietal negativity; Group 3 with right frontal positivity plus left parietal negativity; Group 4 showed no significant association.ConclusionsIn amyloid-confirmed, drug-naïve AD, distinct NPS clusters map onto specific regional amyloid patterns and global clinical profiles. These findings support a network-oriented view of NPS pathophysiology and may inform phenotyping and individualized management.

BackgroundEarly detection of Alzheimer's disease (AD) is critical for timely intervention. Subjective cognitive decline (SCD), defined as self-perceived cognitive worsening while objective performance on standardized tests remains normal, when accompanied by neurodegenerative changes on brain imaging (e.g., hippocampal atrophy), can be classified as SCD with neurodegeneration of AD form (SCD-NDAD). This phenotype may represent an early stage of AD.ObjectiveInvestigate the prevalence and clinical characteristics of SCD-NDAD in general population.Methods: This multicenter, community-based cross-sectional study was conducted from 2013 to 2019 across 31 communities in eight major cities of northern, eastern, southern, and western China. Community-dwelling adults aged 50 years and older were recruited through cluster sampling. Participants underwent standardized interviews, neuropsychological assessments, and magnetic resonance imaging, on the basis of which SCD-NDAD was identified. The prevalence of SCD-NDAD was estimated with age- and sex-standardized weights.ResultsOf 5054 participants (mean age 69.4 years, 60.6% women), 2886 completed MRI. In participants aged ≥50 years, the prevalence of SCD-NDAD was 4.9% (95% confidence interval: 4.1% to 5.8%). In participants aged 65 years and older, prevalence increased to 6.5% (95% confidence interval: 5.5% to 7.7%). While these individuals exhibited preserved cognitive function across all domains, they demonstrated significant hippocampal atrophy, a key marker of AD-related neurodegeneration.ConclusionsSCD-NDAD is common among older adults in China, with an estimated prevalence affecting 12.4 million individuals aged ≥65 years. Identifying this cohort may offer a critical window for early intervention and holds significant implications for public health strategies aimed at dementia prevention.

The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.

BackgroundMemory loss is a core feature of typical Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). Standard memory tests such as word lists assess verbal episodic memory with delayed recall and recognition. However, actual memory fidelity is likely variable, continuous, and has a subjective component.ObjectiveWe investigated dual-processing models of episodic memory (recollection versus familiarity) using confidence ratings in a "judgment of knowing" paradigm (JOK).MethodsThis paradigm was applied to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) memory test as part of neuropsychological evaluation at University of Pittsburgh Alzheimer's Disease Research Center (ADRC), to generate novel indices of memory function to improve sensitivity to early memory problems and provide a memory awareness metric. On recognition testing, participants rated how sure they were of their yes/no responses to each item. We derived novel variables related to memory and metacognition, including an Accuracy-Certainty Index and the Relative Certainty Index.ResultsIn this sample of 347 participants (185 with AD, 55 with MCI, 111 cognitively unimpaired), CERAD Delayed Recall was the best single variable for discriminating groups, although multiple certainty variables also discriminated groups well.ConclusionsThe addition of certainty indices to a standard verbal memory task increased discriminative power between groups, particularly between cognitively normal controls and MCI or AD.

BackgroundIncreasing evidence suggests that the trajectory of Alzheimer's disease (AD) pathologies, such as amyloid and tau, differ between the sexes.ObjectiveGiven the higher susceptibility of females to dementia, we aimed to investigate the sex differences in the primary accumulation of tau and its subsequent spread to later cortical brain regions.MethodsWe included 315 participants in this study: 221 cognitively unimpaired individuals with normal amyloid (n = 140, A- CU) or abnormal amyloid (n = 81, A+ CU), and 94 cognitively impaired individuals with abnormal amyloid (A+ CI). Each individual received two to six tau positron emission tomography (PET) scans using the [18F]-Flortaucipir (FTP) tracer. Linear regression analyses were performed to assess sex-specific tau spreading throughout the Braak stages among three clinical groups.ResultsThe median (interquartile range) age of all samples was 73.5 (68 to 78.2) years. In total, 170 participants (54%) were female. In the A+ CU group, females exhibited higher tau-PET SUVR levels in all Braak I, III-IV, and V-VI. We found that the spreading pattern of tau may vary by sex and AD stages. In the A+ CI individuals, there was an observed interaction between the female sex and baseline tau SUVRs in Braak stages III-IV (p < 0.0001 and Bonferroni-corrected p < 0.0023), affecting longitudinal accumulation of tau in later Braak stages V-VI.ConclusionsOur findings found a sex-specific pattern of tau spreading from Braak stages III-IV to V-VI in A+ CI older adults. This disadvantage may indicate that females might experience faster tau spreading and quicker disease progression when the condition develops to more advanced disease stages.

BackgroundCholinesterase inhibitors (ChEIs) are cornerstones of the symptomatic treatment of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and are also prescribed for vascular dementia (VaD). Despite their widespread use, patterns of ChEI prescribing are unclear.ObjectiveOur objective was to examine the prevalence, timing, and types of ChEI prescriptions before and after dementia diagnosis.MethodsWe analyzed electronic health record and claims data for patients diagnosed with AD, DLB, or VaD between October 2015 and August 2022 from a large U.S. healthcare system. ChEI claims (donepezil, rivastigmine, galantamine) were identified in the ±3 years surrounding dementia diagnosis. Repeated measures logistic regression was used to estimate the likelihood of ChEI fills by time-period, dementia type, and time x dementia type interaction to determine if change in prescription patterns significantly differed by diagnosis.ResultsAmong 3166 eligible patients, DLB had the highest prevalence of ChEIs both pre-and post-diagnosis compared to patients with AD and VaD. Post-diagnosis, donepezil was the most common, while galantamine use was sparse. After adjusting for demographics, patients with VaD had lower rates of ChEIs relative to AD (OR: 0.34, 95% CI 0.26-0.45). In the fully adjusted model, females (OR: 0.81, 95% CI: 0.71-0.91) and patients from ethnoracially minoritized populations (OR: 0.74, 95% CI: 0.62-0.88) were less likely to fill ChEI prescriptions.ConclusionsDonepezil was the most frequently filled ChEI across dementias. Patients with DLB had the highest prevalence of ChEIs pre- and post-diagnosis. The potential disparities in treatment we identified should be investigated further.

Astrocytes are glial cells in the brain essential for maintaining neural homeostasis, modulating synaptic activity through gliotransmission, and supporting metabolic processes. As part of Alzheimer's disease (AD) progression, astrocytes undergo significant morphological and functional changes, transitioning to reactive states that can contribute to both neuroprotection and neurodegeneration. This review aims to summarize current knowledge on the roles of astrocytes in AD, focusing on their contributions to amyloid-β (Aβ) and tau pathologies, neuroinflammation, disrupted calcium signaling, and age-related changes. We synthesized findings from published studies investigating astrocytic sodium channels (Nav1.6), key molecular pathways such as apolipoprotein E (ApoE), oxidative stress, and excitatory amino acid transporter 2 (EAAT2), as well as emerging astrocytic biomarkers including GFAP, YKL-40, and MAO-B. Optogenetic studies and other experimental approaches with high spatiotemporal resolution were also considered to understand astrocyte involvement in circuit impairments and sleep deficits in AD. Astrocytes in AD exhibit altered calcium signaling, impaired gliotransmission, and dysregulated sodium channel activity. Reactive astrocytes influence Aβ and tau pathology, contribute to neuroinflammation, and show altered biomarker expression. Molecular dysfunctions, including changes in ApoE, EAAT2, and oxidative stress pathways, exacerbate disease progression. Emerging therapeutic strategies targeting astrocytic pathways, such as siRNA therapy and gene editing, show promise for mitigating these pathological changes. Understanding the complex roles of astrocytes in AD highlights their dual protective and detrimental functions and identifies novel avenues for therapeutic intervention. Targeting astrocytic dysfunction may offer strategies to slow disease progression and improve cognitive outcomes.