The latest medical research on Geriatric Medicine
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Request AccessPlasma neurofilament light, glial fibrillary acid protein, and phosphorylated tau 181 as biomarkers for neuropsychiatric symptoms and related clinical disease progression.
Journal Alzheimers Research TherapyNeuropsychiatric symptoms (NPS) are common in older people, may occur early in the development of dementia disorders, and have been associated with faster cognitive decline. Here, our objectives were to investigate whether plasma levels of neurofilament light chain (NfL), glial fibrillary acid protein (GFAP), and tau phosphorylated at threonine 181 (pTau181) are associated with current NPS and predict future NPS in non-demented older people. Furthermore, we tested whether the presence of NPS combined with plasma biomarkers are useful to predict Alzheimer's disease (AD) pathology and cognitive decline.
One hundred and fifty-one participants with normal cognition (n = 76) or mild cognitive impairment (n = 75) were examined in a longitudinal brain aging study at the Memory Centers, University Hospital of Lausanne, Switzerland. Plasma levels of NfL, GFAP, and pTau181 along with CSF biomarkers of AD pathology were measured at baseline. NPS were assessed through the Neuropsychiatric Inventory Questionnaire (NPI-Q), along with the cognitive and functional performance at baseline and follow-up (mean: 20 months). Different regression and ROC analyses were used to address the associations of interest.
None of the three plasma biomarker was associated with NPS at baseline. Higher GFAP levels were associated with the presence of NPS at follow-up (OR = 2.8, p = .002) and both, higher NfL and higher GFAP with an increase in the NPI-Q severity score over time (β = 0.25, p = .034 and β = 0.30, p = .013, respectively). Adding NPS and the plasma biomarkers to a reference model improved the prediction of future NPS (AUC 0.72 to 0.88, p = .002) and AD pathology (AUC 0.78 to 0.87, p = .010), but not of cognitive decline (AUC 0.79 to 0.85, p = .081).
Plasma NfL and GFAP are both associated with future NPS and NPS severity change. Considering the presence of NPS along with blood-based AD-biomarkers may improve the prediction of clinical progression of NPS over time and inform clinical decision-making in non-demented older people.
Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults.
N Engl JMany older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission.
In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point.
The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group.
The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.).
Periphery Biomarkers Predicting Conversion of Type 2 Diabetes to Pre-Alzheimer-Like Cognitive Decline: A Multicenter Follow-Up Study.
Journal of Alzheimer's DiseaseThe prevalence of Alzheimer's disease (AD) is increasing, therefore, identifying biomarkers to predict those vulnerable to AD is imperative. Type 2 diabetes (T2D) serves as an independent risk factor for AD. Early prediction of T2D patients who may be more susceptible to AD, so as to achieve early intervention, is of great significance to reduce the prevalence of AD.
To establish periphery biomarkers that could predict conversion of T2D into pre-AD-like cognitive decline.
A follow-up study was carried out from 159 T2D patients at baseline. The correlations of cognitive states (by MMSE score) with multi-periphery biomarkers, including APOE genotype, plasma amyloid-β level, platelet GSK-3β activity, and olfactory score were analyzed by logistic regression. ROC curve was used for establishing the prediction model. Additionally, MRI acquired from 38 T2D patients for analyzing the correlation among cognitive function, biomarkers and brain structure.
Compared with the patients who maintained normal cognitive functions during the follow-up period, the patients who developed MCI showed worse olfactory function, higher platelet GSK-3β activity, and higher plasma Aβ42/Aβ40 ratio. We conducted a predictive model which T2D patients had more chance of suffering from pre-AD-like cognitive decline. The MRI data revealed MMSE scores were positively correlated with brain structures. However, platelet GSK-3β activity was negatively correlated with brain structures.
Elevated platelet GSK-3β activity and plasma Aβ42/Aβ40 ratio with reduced olfactory function are correlated with pre-AD-like cognitive decline in T2D patients, which used for predicting which T2D patients will convert into pre-AD-like cognitive decline in very early stage.
Delaying Brain Aging or Decreasing Tau Levels as Strategies to Prevent Alzheimer's Disease: In Memoriam of Mark A. Smith.
Journal of Alzheimer's DiseaseAging is the main risk for neurodegenerative disorders like Alzheimer's disease. In this short review, I will comment on how delaying brain aging t...
Space-Like Irradiation Exacerbated Cognitive Deficits and Amyloid Pathology in CRND8 Mouse Model of Alzheimer's Disease.
Journal of Alzheimer's DiseaseSpace radiation was linked to neurological damage and behavioral deficits which raised concerns of increased degenerative risk on the brain and development of Alzheimer's disease following space travel.
In this study, we investigated the effects of irradiation by 56Fe and 28Si in CRND8 mice, an Alzheimer's disease mouse model.
Six-month-old CRND8 mice were exposed to whole body irradiation by 56Fe and 28Si at 0.5 Gy and 2 Gy doses. Behavior tests were administered 1-month to 3-months post-irradiation. Amyloid deposition and other pathological changes were analyzed 3-months and/or 6-months post-irradiatio.
The Novel Object Recognition test showed some decline in 8-month-old mice compared to non-irradiated CRND8 mice. Male mice also showed a loss of freezing behavior in the fear conditioning contextual test following irradiation. Golgi staining revealed a loss of spines in hippocampal neurons after irradiation. Total amyloid immunohistochemistry showed a robust increase in 3-months post-irradiation 56Fe groups which became normalized to non-irradiated group by 6-months post-irradiation. However, 2 Gy 28Si caused a trend towards increased plaque load at 3-months post-irradiation which became significant at 6-months post irradiation only in male CRND8 mice. While 0.5 Gy Fe did not induce obvious changes in the total number of iba-1 positive microglia, more hippocampal microglia were found to express PCNA after 0.5 Gy Fe treatment, suggesting potential involvement of microglial dysfunction.
Overall, our study provides new evidence of gender-specific and ion-dependent effects of space radiation on cognition and amyloid pathology in AD models.
Geroscience and the Fight Against Alzheimer's Disease: Between Myth and Reality.
Journal of Alzheimer's DiseaseAging is associated with a gradual decline in cellular stability, leading to a decrease in overall health. In the brain, this process is closely l...
Revealing Molecular Patterns of Alzheimer's Disease Risk Gene Expression Signatures in COVID-19 Brains.
Journal of Alzheimer's DiseaseVarious virus infections are known to predispose to Alzheimer's disease (AD), and a linkage between COVID-19 and AD has been established. COVID-19 infection modulates the gene expression of the genes implicated in progression of AD.
Determination of molecular patterns and codon usage and context analysis for the genes that are modulated during COVID-19 infection and are implicated in AD was the target of the study.
Our study employed a comprehensive array of research methods, including relative synonymous codon usage, Codon adaptation index analysis, Neutrality and parity analysis, Rare codon analyses, and codon context analysis. This meticulous approach was crucial in determining the molecular patterns present in genes up or downregulated during COVID-19 infection.
G/C ending codons were preferred in upregulated genes while not in downregulated genes, and in both gene sets, longer genes have high expressivity. Similarly, T over A nucleotide was preferred, and selection was the major evolutionary force in shaping codon usage in both gene sets. Apart from stops codons, codons CGU - Arg, AUA - Ile, UUA - Leu, UCG - Ser, GUA - Val, and CGA - Arg in upregulated genes, while CUA - Leu, UCG - Ser, and UUA - Leu in downregulated genes were present below the 0.5%. Glutamine-initiated codon pairs have high residual values in upregulated genes. Identical codon pairs GAG-GAG and GUG-GUG were preferred in both gene sets.
The shared and unique molecular features in the up- and downregulated gene sets provide insights into the complex interplay between COVID-19 infection and AD. Further studies are required to elucidate the relationship of these molecular patterns with AD pathology.
Improving Cognition Without Clearing Amyloid: Effects of Tau and Ultrasound Neuromodulation.
Journal of Alzheimer's DiseaseAlzheimer's disease is characterized by progressive impairment of neuronal functions culminating in neuronal loss and dementia. A universal feature...
A Framework for Best Practices and Readiness in the Advent of Anti-Amyloid Therapy for Early Alzheimer's Disease in Asia.
Journal of Alzheimer's DiseaseAdvances in biomarker-based diagnostic modalities, recent approval of anti-amyloid monoclonal antibodies for early Alzheimer's disease (AD; mild co...
Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women.
N Engl JThere are gaps in uptake of, adherence to, and persistence in the use of preexposure prophylaxis for human immunodeficiency virus (HIV) prevention among cisgender women.
We conducted a phase 3, double-blind, randomized, controlled trial involving adolescent girls and young women in South Africa and Uganda. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide (F/TAF), or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF; active control); all participants also received the alternate subcutaneous or oral placebo. We assessed the efficacy of lenacapavir and F/TAF by comparing the incidence of HIV infection with the estimated background incidence in the screened population and evaluated relative efficacy as compared with F/TDF.
Among 5338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 infections among 2134 participants in the lenacapavir group (0 per 100 person-years; 95% confidence interval [CI], 0.00 to 0.19), 39 infections among 2136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76), and 16 infections among 1068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Background HIV incidence in the screened population (8094 participants) was 2.41 per 100 person-years (95% CI, 1.82 to 3.19). HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and than HIV incidence with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P = 0.21), and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). Adherence to F/TAF and F/TDF was low. No safety concerns were found. Injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions.
No participants receiving twice-yearly lenacapavir acquired HIV infection. HIV incidence with lenacapavir was significantly lower than background HIV incidence and HIV incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 1 ClinicalTrials.gov number, NCT04994509.).
Association of enlarged perivascular spaces with cognitive function in dementia-free older adults: A population-based study.
Alzheimers Dementia AmsterdamWe sought to characterize cognitive profiles associated with enlarged perivascular spaces (EPVS) among Chinese older adults.
This population-based study included 1191 dementia-free participants (age ≥60 years) in the MIND-China MRI Substudy (2018-2020). We visually evaluated EPVS in basal ganglia (BG) and centrum semiovale (CSO), white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and cortical superficial siderosis. We used a neuropsychological test battery to assess cognitive function. Data were analyzed using general linear models.
Greater BG-EPVS load was associated with lower z-scores in memory, verbal fluency, and global cognition (p < 0.05); these associations became non-significant when controlling for other cerebral small vessel disease (CSVD) markers (e.g., WMHs, lacunes, and mixed CMBs). Overall, CSO-EPVS load was not associated with cognitive z-scores (p > 0.05); among apolipoprotein E (APOE) -ε4 carriers, greater CSO-EPVS load was associated with lower verbal fluency z-score, even when controlling for other CSVD markers (p < 0.05).
The associations of BG-EPVS with poor cognitive function in older adults are largely attributable to other CSVD markers.
The association of enlarged perivascular spaces (EPVS) with cognitive function in older people is poorly defined.The association of basal ganglia (BG)-EPVS with poor cognition is attributed to other cerebral small vessel disease (CSVD) markers.In apolipoprotein E (APOE) ε4 carriers, a higher centrum semiovale (CSO)-EPVS load is associated with poorer verbal fluency.
Plasma pTau181 enhances the prediction of future clinical decline in amyloid-positive mild cognitive impairment.
Alzheimers Dementia AmsterdamPlasma pTau181, a marker of amyloid and tau burden, was evaluated as a prognostic predictor of clinical decline and Alzheimer's disease (AD) progression of amyloid-positive (Aβ+) patients with mild cognitive impairment (MCI). The training cohort for constructing the Bayesian prediction models comprised 135 Aβ+ MCI clinical trial placebo subjects. Performance was evaluated in two validation cohorts. An 18-month ≥1 increase in the Clinical Dementia Rating Sum of Boxes was the clinical decline criterion. Baseline plasma pTau181 concentration matched clinical assessments' prediction performance. Adding pTau181 to clinical assessments significantly improved the prediction of an 18-month clinical decline and the 36-month progression from Aβ+ MCI to AD. The area under the receiver operating characteristic curve for the latter increased from 71.8% to 79%, and the hazard ratio for time-to-progression improved from 2.26 to 3.11 (p < 0.0001). Baseline plasma pTau181 has the potential for identifying Aβ+ MCI subjects with faster clinical decline over time.
This study assessed pTau181 as a prognostic predictor of 18-month clinical decline and extended progression to Alzheimer's disease (AD) in amyloid-positive patients with mild cognitive impairment (Aβ+ MCI).The research findings underscore the promise of baseline plasma pTau181 as a screening tool for identifying Aβ+ MCI individuals with accelerated clinical decline within a standard 18-month clinical trial period. The predictive accuracy is notably enhanced when combined with clinical assessments.Similar positive outcomes were noted in forecasting the extended progression of Aβ+ MCI subjects to AD.
