Journal of Alzheimer's Disease最新文献

Background: Anosognosia or lack of insight is a common feature of Alzheimer's disease (AD) and associated disorders. It is an impairment in the ability to recognize the disease and related symptoms. Anosognosia is associated among patients with poor compensatory strategies, behavioral disorders, apathy and caregiver burden. Therefore, its early identification by healthcare workers is a major challenge in order to provide support for both patients and caregivers.

Objective: To explore the knowledge, attitudes and experiences of French healthcare workers relating to anosognosia in AD and related disorders.

Methods: An online self-completed questionnaire was created for the study. It was anonymous and divided into three dimensions: general knowledge, confidence, and subjective experiences of anosognosia. One hundred and eleven healthcare workers completed the questionnaire. Mann Whitney and Kruskal Wallis tests were used to determine the variables associated with the total knowledge and confidence scores. Ordinal logistic regressions were performed to explore the associations between subjective experiences and demographics.

Results: The participants had moderate knowledge. Knowledge scores were influenced by their experience in the geriatric field, type of profession, workplaces and training. The areas where knowledge was poorest were anosognosia assessment and management. The participants with the lowest knowledge levels were those interacting the most with patients, especially at home. Overall, they identified difficulties related to anosognosia and did not seem confident about their ability to deal with this condition.

Conclusions: This study determines specific areas for training on anosognosia, such as identification, assessment and management of this condition.

Background: Blood pressure (BP) variability (BPV) and time in target range (TTR) are emerging vascular risk factors for dementia, independent of traditionally targeted mean BP.

Objective: Determine whether BPV or TTR is most strongly associated with cognitive risk.

Methods: In this post hoc analysis of the SPRINT trial, 8034 participants underwent repeated BP measurement and cognitive testing at baseline and follow-up. Visit-to-visit BPV was calculated as average real variability. TTR was the percent of time in desired treatment arm target range (standard: 120-140 mmHg systolic BP; intensive: 110-130 mmHg systolic BP). Adjudicated clinical outcomes were no cognitive impairment, mild cognitive impairment (MCI), and probable dementia. We investigated a direct comparison of BPV and TTR in predicting cognitive risk, stratified by BP treatment group.

Results: Elevated BPV was associated with increased risk for MCI (adjusted HR: 1.21 [95% CI 1.10, 1.33], p < 0.001) and MCI/dementia (HR: 1.17 [95% CI 1.07, 1.27], p < 0.001) in the standard group, and dementia (HR: 1.17 [95% CI 1.01, 1.36], p = 0.039) in the intensive group. Higher TTR was related to lower dementia risk (HR: 0.72 [95% CI 0.60, 0.86], p < 0.001) in the intensive group only.

Conclusions: Visit-to-visit BPV outperformed TTR in predicting risk for MCI and MCI/dementia. TTR was more strongly associated with dementia risk under intensive treatment. Findings were independent of mean BP in a cohort with rigorously controlled BP and suggest newer aspects of BP control may be harnessed to further reduce cognitive risk.

Clinical trial information: ClinicalTrials.gov; NCT01206062.

Background: Although Boston Naming Test has been thoroughly validated at a global level, there is limited assessment of item-level properties using modern psychometric methods.

Objective: This study aimed to investigate the construct validity and item-level properties of the color-picture version of Boston Naming Test (CP-BNT) in a Chinese cohort with neurodegenerative diseases.

Methods: This retrospective study included 424 participants, consisting of 118 normal controls, 152 with Alzheimer's disease, 101 with primary progressive aphasia, and 53 with other neurodegenerative diseases. All participants underwent a comprehensive neuropsychological assessment that included the CP-BNT. Factor analysis and item response theory were conducted.

Results: The CP-BNT exhibits a multidimensional structure with three factors: Factor 1, consisting of nine items with moderate difficulty levels, demonstrated peak measurement function for mild anomia (the highest information value = 33.7, ability estimated value = -0.8, reliability = 0.97); Factor 2, comprising eleven items with lower difficulty levels, performed well in cases of mild to moderate anomia (the highest information value = 34.1, ability estimated value = -1.2, reliability = 0.97); and Factor 3, including ten items with higher difficulty levels, provided the most measurement information for normal naming (the highest information value = 9.9, ability estimated value = 0, reliability = 0.90). All items, except item igloo, showed good discrimination (discrimination parameter ranged from 5.46 to 1.15). Most items had a different difficulty position versus the original version, thereby generating a novel item sequence with an ascending difficulty hierarchy for Chinese samples.

Conclusions: These findings support that the CP-BNT has good validity, reliability, and cultural appropriateness in the Chinese context, improving its utility in clinical assessments and interventions.

Background: In older adults with preclinical Alzheimer's disease (AD), learning curves derived from validated psychological learning paradigms are reduced to an extent greater than impairment, or decline, on neuropsychological memory tests.

Objective: This study aimed to examine how age, sex, education, mood, and general dementia risk, which also increases risk for preclinical AD, could influence learning curves.

Methods: 1050 adults enrolled in the BetterBrains trial completed 10 blocks of ORCA-LLT learning trials over 5 days. Learning curves were derived from improvement in accuracy over trials. Participants also completed questionnaires of demography and mood, and the CAIDE risk score was computed for each participant.

Results: Most participants (67%) completed ≥6 blocks of ORCA-LLT. Older age (d = 0.75), lower education (d = 0.50), and higher dementia risk (d = 0.36) were associated significantly with slower learning rates.

Conclusions: In older adults, learning curves are influenced subtly by age, education, and dementia risk but not by sex or mood.

Background: Although COVID-19 has been linked to worse acute outcomes in patients with some neurodegenerative disorders, its long-term impact on dementia remains unclear.

Objective: To investigate the outcomes of COVID-19 survivors with dementia.

Methods: This retrospective study evaluated 9806 patients with dementia in the Montefiore Health System (January 2016 to July 2023). Comparisons were made between dementia patients with and without a positive SARS-CoV-2 polymerase-chain-reaction test who had a follow-up at least two weeks post-infection. Outcomes included all-cause mortality, major adverse cardiovascular events (MACE), new-onset dysphagia, dyspnea, fatigue, new-onset sleep disturbances, altered mental status, first-time fall, headache, new-onset depression, and new-onset anxiety. Adjusted hazard ratios (aHR) were computed adjusting for age, sex, race, ethnicity, and pre-existing comorbidities.

Results: Dementia patients with COVID-19 were younger, more likely to be male, and had a higher prevalence of major pre-existing comorbidities compared to those without COVID-19. Patients who survived acute COVID-19 were more likely to die than non-COVID controls after adjusting for covariates (aHR = 1.65 [1.43, 1.91]). COVID-19 was significantly associated with higher risk of MACE (aHR = 1.58 [1.41, 1.78]), new-onset dysphagia (aHR = 1.64 [1.42, 1.91]), dyspnea (aHR = 1.27 [1.12, 1.44]), fatigue (aHR = 1.42 [1.22, 1.65]), new-onset sleep disturbances (aHR = 1.36 [1.15, 1.60]), altered mental status (aHR = 1.36 [1.16, 1.59]), and first-time fall (aHR = 1.34 [1.09, 1.65]).

Conclusions: COVID-19 increases the risk of mortality and other adverse health outcomes in dementia patients. These findings highlight the need for closer follow-up and management strategies for dementia patients post-COVID-19.

Background: It has been hypothesized that insulin resistance is pivotal in mediating amyloid and tau dysregulations in Alzheimer's disease (AD).

Objective: To investigate the impact of different antidiabetic agents, their daily dosage intake, and treatment duration on cerebrospinal fluid (CSF) AD biomarkers among patients with type 2 diabetes.

Methods: This cross-sectional study selected patients between 50 and 80 years with diabetes and CSF AD biomarkers screened between 2017 and 2023 in the VALCODIS Cohort. CSF biomarkers were total tau (t-tau), phosphorylated tau 181 (p-tau), and amyloid-β 42 (Aβ₄₂). Analytical variables were obtained. Antidiabetic prescriptions were recorded in defined daily doses (DDD), according to the ATC/DDD 2021 system, and years of drug exposure duration before lumbar puncture. Logistic regressions were performed to establish the correlations between drug usage and AD biomarker alteration.

Results: Among patients with diabetes, Insulin consumption was associated with lower odds of abnormal Aβ₄₂ levels (OR 0.36 [95% CI 0.15, 0.76]) and tau pathology (OR 0.49 [95% CI 0.24-0.98]). Metformin was related to lower odds of pathological p-tau when diabetes was uncontrolled, acting on t-tau and t-tau/Aβ₄₂ ratio when it was concomitant with insulin, and patients had controlled diabetes. Lower odds of pathological levels of tau were observed when additional oral antidiabetic drugs were added among metformin users. iSGLT2 was associated with tau pathology.

Conclusions: The impact of antidiabetics on AD-related pathological biomarkers may depend on diabetes management.

Background: To date, the effect of tau phosphorylation at different amino acid sites on the conformation and function of tau is still unclear in Alzheimer's disease (AD). Protein fingerprinting, also known as the protein folding shape code (PFSC) method, is a protein structure prediction technique based on protein sequence, which can reveal proteins' most likely spatial conformation.

Objective: To investigate the effect of phosphorylation on tau protein conformation using PFSC technology and further analyze the differences in the effect of phosphorylation on tau aggregation at specific sites.

Methods: We performed a conformational analysis of wild-type and simulated mutant hTau441 using the PFSC method and synthesized the phosphorylated and non-phosphorylated tau fragments by the chemical solid phase method.

Results: We found that the number of Ser262 protein fingerprints increased from six in tau S262A to nine in tau S262E, together with increased conformational changes and enhanced flexibility. The in vitro Thioflavin S assay showed that phosphorylated tau fragments R1-pS262 possessed a stronger activity of inducing tau aggregation. In contrast to the non-phosphorylated tau fragment R1-nS262, R1-pS262 promoted endogenous tau aggregation and decreased synaptic proteins. In rats, R1-pS262 caused cognitive impairments and neuronal loss in addition to endogenous tau aggregation and synaptic damage.

Conclusions: Our study firstly reports that tau phosphorylation at Ser262 induces tau aggregation, and phosphorylated tau fragments R1-pS262 directly result in neuropathological changes. These provide new clues to the pathogenesis of tauopathy, such as AD, and a new molecular target for possible intervention.

Background: Changes in the Alzheimer's disease-related apolipoprotein genes expression, occurring parallel with brain ischemia-induced neurodegeneration in the hippocampal CA3 area, may be crucial for the development of memory loss and dementia.

Objective: The aim of the study was to investigate changes in genes expression of apolipoprotein A1 (APOA1), apolipoprotein E (APOE), and clusterin (CLU) in CA3 area post-ischemia with survival of 2 years.

Methods: The gene expression was evaluated with the use of an RT-PCR protocol after 2, 7, and 30 days and 6, 12, 18, and 24 months post-ischemia.

Results: The expression of the APOA1 gene (encoding apolipoprotein A1) was below the control values at 2 days, 6 and 12 months while at 7 and 30 days and 18 and 24 months post-ischemia this gene expression exceeded the control values. In the case of the CLU gene (encoding clusterin) expression, it was above the control values at all times post-ischemia. Similar expression was observed for the APOE gene (encoding apolipoprotein E) except on day 7 after ischemia where its expression was below the control value.

Conclusions: The results seem to indicate that the observed changes in the gene expression may reflect the activation and inhibition of a variety of processes involved in ischemia-induced neurodegeneration. The enhanced expression of APOA1 and CLU genes may be associated with induction of neuroprotective mechanisms while increased expression of the APOE gene may produce detrimental effects.

Background: Amyloid-β (Aβ) and hyperphosphorylated tau are crucial biomarkers in Alzheimer's disease (AD) pathogenesis, interacting synergistically to accelerate disease progression. While Aβ initiates cascades leading to tau hyperphosphorylation and neurofibrillary tangles, PET imaging studies suggest a sequential progression from amyloidosis to tauopathy, closely linked with neurocognitive symptoms.

Objective: To analyze the complex interactions between Aβ and tau in AD using probabilistic graphical models, assessing how regional tau accumulation is influenced by Aβ burden.

Methods: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Anti-Aβ Treatment in Asymptomatic Alzheimer's (A4) study were utilized, involving participants across various cognitive stages and employing both Florbetapir and Flortaucipir as tracers. Tau standardized uptake value ratio values were harmonized across studies, and participants were stratified into quantile groups based on Aβ levels. A LASSO regularized Gaussian graphical model analyzed partial correlations among brain regions to discern patterns of tau accumulation across different Aβ levels.

Results: Statistical analyses revealed significant differences in tau structure among low, medium, and high Aβ groups in both ADNI and A4 cohorts, with graph metrics, such as small-world coefficient, indicating increased tau efficiency as Aβ burden increased.

Conclusions: Our findings indicate that tau accumulates more efficiently with increasing Aβ burden, highlighting an interplay that could inform development of dual-targeting therapies in AD. This study underscores the importance of Aβ and tau interactions in AD progression and supports the hypothesis that targeting both pathologies could be crucial for therapeutic interventions.

Background: Gantenerumab is a fully human anti-amyloid-β (Aβ) immunoglobulin G1 monoclonal antibody for subcutaneous (SC) administration. The efficacy and safety of low-dose (105 mg or 225 mg) gantenerumab were investigated in SCarlet RoAD (SR; NCT01224106), a Phase III, double-blind (DB), placebo-controlled study in participants with prodromal Alzheimer's disease. Following a pre-planned futility analysis, SR was converted into an open-label extension (OLE) study.

Objective: To assess the long-term safety and tolerability of SC gantenerumab at doses of up to 1200 mg every 4 weeks (Q4W) in OLE participants who previously received placebo or gantenerumab in the DB part of SR.

Methods: Participants of the DB part of SR, who met the eligibility criteria for the OLE, were offered the opportunity to receive gantenerumab up-titrated to 1200 mg Q4W according to prespecified titration regimens. Safety and tolerability were assessed using magnetic resonance imaging (MRI), physical and neurologic examinations, and adverse event monitoring.

Results: Overall, 154 participants were rolled over from the DB part of SR and received at least one dose of gantenerumab in the SR OLE. The median duration of treatment was 2.9 years (152.9 weeks). Forty-seven (30.5%) participants had an amyloid-related imaging abnormalities - edema (ARIA-E) MRI finding, and 51 (33.1%) had an ARIA - hemorrhage MRI finding. Most ARIA-E findings were asymptomatic and manageable by MRI monitoring and dose intervention. There were no unexpected safety findings.

Conclusions: SC gantenerumab at doses of up to 1200 mg Q4W was well tolerated with no unexpected safety findings in participants with prodromal Alzheimer's disease.Trial registration: ClinicalTrials.gov ID NCT01224106.