@article {pmid39044502,
year = {2024},
author = {Wu, HS and Li, L and Sun, QQ and Tan, CC and Tan, L and Xu, W},
title = {Predicting Cognitive Decline for Non-Demented Adults with High Burden of Tau Pathology, Independent of Amyloid Status.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {908-916},
doi = {10.14283/jpad.2024.82},
pmid = {39044502},
issn = {2426-0266},
mesh = {Humans ; Female ; Male ; *Cognitive Dysfunction/cerebrospinal fluid/diagnosis ; Aged ; *tau Proteins/cerebrospinal fluid ; Longitudinal Studies ; Amyloid beta-Peptides/cerebrospinal fluid ; Cross-Sectional Studies ; Biomarkers/cerebrospinal fluid ; Nomograms ; Mental Status and Dementia Tests ; Middle Aged ; },
abstract = {BACKGROUND: Abnormal tau proteins are independent contributors to cognitive impairment. Nevertheless, not all individuals exposed to high-level tau pathology will develop cognitive dysfunction. We aimed to construct a model to predict cognitive trajectory for this high-risk population.

METHOD: Longitudinal data of 181 non-demented adults (mean age= 73.1; female= 45%), who were determined to have high cerebral burden of abnormal tau by cerebrospinal fluid (CSF) measurements of phosphorylated tau (ptau181) or total tau, were derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Cognitive decline was defined as Mini-Mental State Examination scores decline ≥ 3 over three years. A predictive nomogram was constructed using stepwise backward regression method. The discrimination, calibration, and clinical usefulness of the nomogram were evaluated. The model was validated in another 189 non-demented adults via a cross-sectional set (n=149, mean age = 73.9, female = 51%) and a longitudinal set (n= 40, mean age = 75, female = 48%). Finally, the relationships of the calculated risk scores with cognitive decline and risk of Alzheimer's disease were examined during an extended 8-year follow-up.

RESULT: Lower volume of hippocampus (odds ratio [OR] = 0.37, p< 0.001), lower levels of CSF sTREM2 (OR = 0.76, p = 0.003), higher scores of Alzheimer's Disease Assessment Scale-Cognitive (OR = 1.15, p = 0.001) and Functional Activities Questionnaire (OR = 1.16, p = 0.016), and number of APOE ε4 (OR = 1.88, p = 0.039) were associated with higher risk of cognitive decline independent of the amyloid status and were included in the final model. The nomogram had an area of under curve (AUC) value of 0.91 for training set, 0.93 for cross-sectional validation set, and 0.91 for longitudinal validation set. Over the 8-year follow-up, the high-risk group exhibited faster cognitive decline (p< 0.001) and a higher risk of developing Alzheimer's dementia (HR= 6.21, 95% CI= 3.61-10.66, p< 0.001).

CONCLUSION: APOE ε4 status, brain reserve capability, neuroinflammatory marker, and neuropsychological scores can help predict cognitive decline in non-demented adults with high burden of tau pathology, independent of the presence of amyloid pathology.},
}

Humans
Female
Male
*Cognitive Dysfunction/cerebrospinal fluid/diagnosis
Aged
*tau Proteins/cerebrospinal fluid
Longitudinal Studies
Amyloid beta-Peptides/cerebrospinal fluid
Cross-Sectional Studies
Biomarkers/cerebrospinal fluid
Nomograms
Mental Status and Dementia Tests
Middle Aged

@article {pmid39044501,
year = {2024},
author = {Reed, AM and Duff, K and Dibble, LE and Paul, SS and Hooyman, A and Schaefer, SY},
title = {Examining the Diagnostic Accuracy of a Novel Performance-Based Test for Alzheimer's Disease Screening.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {903-907},
doi = {10.14283/jpad.2024.93},
pmid = {39044501},
issn = {2426-0266},
mesh = {Humans ; *Alzheimer Disease/diagnosis ; Female ; Aged ; Male ; *Parkinson Disease/diagnosis ; Sensitivity and Specificity ; Neuropsychological Tests ; Aged, 80 and over ; ROC Curve ; Upper Extremity/physiopathology ; },
abstract = {Affordable, rapid methods for identifying mild Alzheimer's disease (AD) are needed. A simple, brief performance-based test involving the learning of functional upper-extremity movements has been developed and is associated with AD pathology and functional decline. However, its specificity to AD relative to other neurodegenerative diseases that present with motor impairment is unknown. This study examined whether this novel test could distinguish between 34 participants diagnosed with mild AD (Clinical Dementia Rating Scale = 0.5-1) from 23 participants with mild-to-moderate Parkinson's disease (PD) (Hoehn and Yahr = 2-3) using Receiver Operating Characteristic analysis of secondary data from two separate clinical trials. Indicators of diagnostic accuracy demonstrated that the test identified participants with AD, who had worse scores than those with PD, suggesting it may be a viable screening tool for mild AD. Exploratory analyses with a control group (n=52) further showed that test scores were not sensitive to motor dysfunction.},
}

Humans
*Alzheimer Disease/diagnosis
Female
Aged
Male
*Parkinson Disease/diagnosis
Sensitivity and Specificity
Neuropsychological Tests
Aged, 80 and over
ROC Curve
Upper Extremity/physiopathology

@article {pmid39044500,
year = {2024},
author = {Korologou-Linden, R and Kalsi, J and Kafetsouli, D and Olawale, A and Iwata, A and Wingfield, D and Mummery, D and Hayhoe, B and Robinson, O and Majeed, A and Middleton, LT},
title = {Novel Blood-Based Biomarkers and Disease Modifying Therapies for Alzheimer's Disease. Are We Ready for the New Era?.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {897-902},
doi = {10.14283/jpad.2024.83},
pmid = {39044500},
issn = {2426-0266},
mesh = {*Alzheimer Disease/diagnosis/drug therapy ; Humans ; *Biomarkers/cerebrospinal fluid/blood ; Positron-Emission Tomography ; Amyloid beta-Peptides/cerebrospinal fluid ; Antibodies, Monoclonal/therapeutic use ; },
abstract = {Recent positive trials for novel disease modifying therapies of anti-amyloid monoclonal antibodies represent a paradigm shift in the prevention and management of Alzheimer's disease, a relentlessly progressive and debilitating disease of old age. The reported efficacy of these new agents when given early in the disease trajectory is dependent on an early and accurate disease diagnosis, which is currently based on cerebrospinal fluid tests or/and neuro-imaging studies such as positron emission tomography. These confirmatory tests provide in vivo evidence of the pathological signature of Alzheimer's disease, of increased cerebral amyloid and tau burden and neurodegeneration. The emergence of blood-based biomarkers represents another breakthrough, offering a less invasive and scalable diagnostic tool that could be applied in both primary and specialist care settings, potentially revolutionizing Alzheimer's disease clinical pathways. However, healthcare systems face challenges in the adoption of these new technologies and therapies due to diagnostic and treatment capacity constraints, as well as financial and infrastructure requirements.},
}

*Alzheimer Disease/diagnosis/drug therapy
Humans
*Biomarkers/cerebrospinal fluid/blood
Positron-Emission Tomography
Amyloid beta-Peptides/cerebrospinal fluid
Antibodies, Monoclonal/therapeutic use

@article {pmid39044499,
year = {2024},
author = {Zhou, RZ and Wimo, A and Winblad, B},
title = {Editorial: On the 2024 Alzheimer's Association Criteria: Still Not Ready for Clinical Use.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {895-896},
doi = {10.14283/jpad.2024.141},
pmid = {39044499},
issn = {2426-0266},
mesh = {Humans ; *Alzheimer Disease/diagnosis ; },
}

Humans
*Alzheimer Disease/diagnosis

@article {pmid39044498,
year = {2024},
author = {Jimenez-Maggiora, GA and Schulz, AP and Donohue, MC and Qiu, H and Jaiswal, SN and Adegoke, O and Gallardo, R and Baryshnikava, O and Rissman, RA and Abdel-Latif, S and Sperling, RA and Aisen, PS},
title = {Maximizing the Utility of Alzheimer's Disease Trial Data: Sharing of Baseline A4 and LEARN Data.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {889-894},
doi = {10.14283/jpad.2024.120},
pmid = {39044498},
issn = {2426-0266},
mesh = {*Alzheimer Disease ; Humans ; *Information Dissemination ; Longitudinal Studies ; Aged ; Neuroimaging ; Male ; Female ; Randomized Controlled Trials as Topic ; Antibodies, Monoclonal, Humanized ; },
abstract = {BACKGROUND: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies were conducted between 2014 and 2023, with enrollment completed in 2017 and final study results reported in 2023. The study screening process involved the collection of initial clinical, cognitive, neuroimaging, and genetic measures to determine eligibility. Once randomized, enrolled participants were assessed every four weeks over a 4.5-year follow-up period during which longitudinal clinical, cognitive, and neuroimaging measures were collected. A large number of longitudinal fluid biospecimens were also collected and banked. Consistent with the NIH data sharing policy and the principles of Open Science, the A4/LEARN investigators aimed to share data as broadly and early as possible while still protecting participant privacy and confidentiality and the scientific integrity of the studies.

OBJECTIVES: We describe the approach, methods, and platforms used to share the A4 and LEARN pre-randomization study data for secondary research use. Preliminary results measuring the impact of these efforts are also summarized. We conclude with a discussion of lessons learned and next steps.

DESIGN: The materials shared included de-identified quantitative and image data, analysis software, instruments, and documentation.

SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan, and Australia.

PARTICIPANTS: The A4 study screened (n=6763), enrolled, and randomized (n=1169) participants between the ages of 65 and 85 with a blinded follow-up period of 240 weeks followed by an open-label period of variable length. The LEARN study screened and enrolled individuals (n=538) who were ineligible for the A4 study based on nonelevated measures of amyloid accumulation using positron emission tomography imaging (amyloid PET).

MEASUREMENTS: We provide descriptive measures of the data shared and summarize the frequency, characteristics, and status of all data access requests submitted to date. We evaluate the scientific impact of the data-sharing effort by conducting a literature search to identify related publications.

RESULTS: The A4 and LEARN pre-randomization study data were released in December 2018. As of May 8, 2024, 1506 requests have been submitted by investigators and citizen scientists from more than 50 countries. We identified 49 peer-reviewed publications that acknowledge the A4/LEARN study.

CONCLUSIONS: Our initial results provide evidence supporting the feasibility and scientific utility of broad and timely sharing of Alzheimer's disease trial data.},
}

*Alzheimer Disease
Humans
*Information Dissemination
Longitudinal Studies
Aged
Neuroimaging
Male
Female
Randomized Controlled Trials as Topic
Antibodies, Monoclonal, Humanized

@article {pmid39044497,
year = {2024},
author = {Boyle, R and Klinger, HM and Shirzadi, Z and Coughlan, GT and Seto, M and Properzi, MJ and Townsend, DL and Yuan, Z and Scanlon, C and Jutten, RJ and Papp, KV and Amariglio, RE and Rentz, DM and Chhatwal, JP and Donohue, MC and Sperling, RA and Schultz, AP and Buckley, RF},
title = {Left Frontoparietal Control Network Connectivity Moderates the Effect of Amyloid on Cognitive Decline in Preclinical Alzheimer's Disease: The A4 Study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {881-888},
doi = {10.14283/jpad.2024.140},
pmid = {39044497},
issn = {2426-0266},
mesh = {Humans ; Female ; *Alzheimer Disease ; Male ; Aged ; *Cognitive Dysfunction ; *Magnetic Resonance Imaging ; *Amyloid beta-Peptides/metabolism ; *Parietal Lobe/diagnostic imaging ; Longitudinal Studies ; *Frontal Lobe/diagnostic imaging ; Positron-Emission Tomography ; Prodromal Symptoms ; Nerve Net/diagnostic imaging/physiopathology ; },
abstract = {BACKGROUND: Stronger resting-state functional connectivity of the default mode and frontoparietal control networks has been associated with cognitive resilience to Alzheimer's disease related pathology and neurodegeneration in smaller cohort studies.

OBJECTIVES: We investigated whether these networks are associated with longitudinal CR to AD biomarkers of beta-amyloid (Aβ).

DESIGN: Longitudinal mixed.

SETTING: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study and its natural history observation arm, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.

PARTICIPANTS: A sample of 1,021 cognitively unimpaired older adults (mean age = 71.2 years [SD = 4.7 years], 61% women, 42% APOEε4 carriers, 52% Aβ positive).

MEASUREMENTS: Global cognitive performance (Preclinical Alzheimer's Cognitive Composite) was assessed over an average 5.4 year follow-up period (SD = 2 years). Cortical Aβ and functional connectivity (left and right frontoparietal control and default mode networks) were estimated from fMRI and PET, respectively, at baseline. Covariates included baseline age, APOEε4 carrier status, years of education, adjusted gray matter volume, head motion, study group, cumulative treatment exposure, and cognitive test version.

RESULTS: Mixed effects models revealed that functional connectivity of the left frontoparietal control network moderated the negative effect of Aβ on cognitive change (p = .025) such that stronger connectivity was associated with reduced Aβ-related cognitive decline.

CONCLUSIONS: Our results demonstrate a potential protective effect of functional connectivity in preclinical AD, such that stronger connectivity in this network is associated with slower Aβ-related cognitive decline.},
}

Humans
Female
*Alzheimer Disease
Male
Aged
*Cognitive Dysfunction
*Magnetic Resonance Imaging
*Amyloid beta-Peptides/metabolism
*Parietal Lobe/diagnostic imaging
Longitudinal Studies
*Frontal Lobe/diagnostic imaging
Positron-Emission Tomography
Prodromal Symptoms
Nerve Net/diagnostic imaging/physiopathology

@article {pmid39044496,
year = {2024},
author = {Raman, R and Hussen, K and Donohue, MC and Ernstrom, K and Holdridge, KC and Langford, O and Molina-Henry, DP and Pierce, AL and Sims, JR and Smith, A and Yaari, R and Aisen, PS and Sperling, R and Grill, JD},
title = {Pre-Randomization Predictors of Study Discontinuation in a Preclinical Alzheimer's Disease Randomized Controlled Trial.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {874-880},
doi = {10.14283/jpad.2024.136},
pmid = {39044496},
issn = {2426-0266},
mesh = {Humans ; *Alzheimer Disease ; Male ; Female ; Aged ; Patient Dropouts/statistics & numerical data ; COVID-19 ; Prodromal Symptoms ; Australia ; United States ; Canada ; Positron-Emission Tomography ; Aged, 80 and over ; },
abstract = {BACKGROUND: Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment.

OBJECTIVE: This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study.

DESIGN: All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers).

SETTING: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic.

PARTICIPANTS: The sample consisted of all 1169 A4 trial randomized participants.

MEASUREMENTS: Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p<0.10 were then included in a multivariable GLMM.

RESULTS: Among randomized participants, 339 (29%) discontinued the study during the blinded period (median follow-up time in trial: 759 days). From the multivariable analysis, the two main predictors of study discontinuation were screening State-Trait Anxiety Inventory (STAI) scores (OR = 1.07 [95%CI = 1.02; 1.12]; p=0.002) and age (OR = 1.06 [95%CI = 1.03; 1.09]; p<0.001). Participants with a family history of dementia (OR = 0.75 [95%CI = 0.55; 1.01]; p=0.063) and APOE ε4 carriers (OR = 0.79 [95%CI = 0.6; 1.04]; p=0.094) were less likely to discontinue from the study, with the association being marginally significant. In these analyses, sex, race and ethnicity, cognitive scores and amyloid/tau PET scores were not associated with study dropout.

CONCLUSIONS: In the A4 trial, older participants and those with higher levels of anxiety at baseline as measured by the STAI were more likely to discontinue while those who had a family history of dementia or were APOE ε4 carriers were less likely to drop out. These findings have direct implications for future preclinical trial design and selection processes to identify those individuals at greatest risk of dropout and provide information to the study team to develop effective selection and retention strategies in AD prevention studies.},
}

Humans
*Alzheimer Disease
Male
Female
Aged
Patient Dropouts/statistics & numerical data
COVID-19
Prodromal Symptoms
Australia
United States
Canada
Positron-Emission Tomography
Aged, 80 and over

@article {pmid39044495,
year = {2024},
author = {Shirzadi, Z and Schultz, AP and Properzi, M and Yaari, R and Yau, WW and Brickman, AM and Rafii, MS and Donohue, MC and Ernstrom, K and Wang, S and Jack, CR and Greenberg, SM and Raman, R and Aisen, P and Sperling, RA and Chhatwal, JP},
title = {Greater White Matter Hyperintensity Volume Is Associated with the Number of Microhemorrhages in Preclinical Alzheimer's Disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {869-873},
doi = {10.14283/jpad.2024.139},
pmid = {39044495},
issn = {2426-0266},
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/drug therapy ; Female ; Male ; Aged ; *White Matter/pathology/diagnostic imaging/drug effects ; *Magnetic Resonance Imaging ; Double-Blind Method ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Prodromal Symptoms ; },
abstract = {BACKGROUND: Increased white matter hyperintensity (WMH) volume visible on MRI is a common finding in Alzheimer's disease (AD). We hypothesized that WMH in preclinical AD is associated with the presence of advanced vessel amyloidosis manifested as microhemorrhages (MCH).

OBJECTIVES: 1) To assess the relationship between baseline WMH volume and baseline MCH. 2) To assess the relationship between longitudinal WMH accumulation and last MRI MCH during the double-blind phase of the A4 trial.

DESIGN: A multicenter, randomized, double-blind, placebo-controlled, Phase 3 study comparing solanezumab with placebo given as infusions once every 4 weeks over 4.5 years in subjects with preclinical AD, defined as having evidence of elevated brain amyloid before the stage of clinically evident cognitive impairment, with an optional open-label extension period.

SETTING: Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study.

PARTICIPANTS: A sample of 1157 cognitively unimpaired older adults (mean age = 71.9 years [SD = 4.8 years], 59% women, 59% APOE ε4 carriers).

MEASUREMENTS: A linear regression model was used to assess the impact of baseline MCH amount (0, 1, 2+) on WMH volume. A linear mixed-effects model was used to assess the impact of last MRI MCH on longitudinal WMH. All models were corrected for age, sex, grey matter volume, cortical amyloid PET, APOE ε4 status, and treatment group.

RESULTS: Baseline WMH volume was greater in individuals with more than one MCH compared to those with no MCH (t=4.8, p<0.001). The longitudinal increase in WMH amongst individuals with one (t=2.3, p=0.025) and more than one MCH (t=6.7, p<0.001) at the last MRI was greater than those with no MCH.

CONCLUSION: These results indicate a strong association between WMH and MCH, a common manifestation of cerebral amyloid angiopathy and ARIA-H. These results suggest that increased WMH volume may represent an early sign of vessel amyloidosis, likely prior to the emergence of MCH.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/drug therapy
Female
Male
Aged
*White Matter/pathology/diagnostic imaging/drug effects
*Magnetic Resonance Imaging
Double-Blind Method
*Antibodies, Monoclonal, Humanized/therapeutic use
Prodromal Symptoms

@article {pmid39044494,
year = {2024},
author = {Yaari, R and Holdridge, KC and Mancini, M and Rafii, MS and Case, M and Battioui, C and Sims, JR and Aisen, PS and Sperling, RA},
title = {Safety Profile of a Cognitively Unimpaired Older Population with Elevated Cerebral Amyloid in a 4.5-Year Clinical Trial.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {857-868},
doi = {10.14283/jpad.2024.138},
pmid = {39044494},
issn = {2426-0266},
mesh = {Humans ; Aged ; Female ; Male ; *Positron-Emission Tomography ; Aged, 80 and over ; *Aniline Compounds/therapeutic use/adverse effects ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Brain/diagnostic imaging/metabolism ; Ethylene Glycols ; Double-Blind Method ; Amyloid beta-Peptides/metabolism ; },
abstract = {BACKGROUND: Preclinical Alzheimer's disease is increasingly studied in clinical trials. Although safety signals are routinely monitored in clinical trial populations with Alzheimer's disease, it can be challenging to identify new safety signals against background rates of age-related medical comorbidities.

OBJECTIVES: To report detailed safety data from a cognitively unimpaired older population with evidence of elevated cerebral amyloid levels on amyloid positron emission tomography in the placebo arm of a Phase 3 clinical trial.

DESIGN: Phase 3, 4.5-year, multicenter, placebo-controlled trial.

SETTING: Placebo data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study.

PARTICIPANTS: Enrolled participants were aged 65-85 years with a global Clinical Dementia Rating score of 0, a Mini-Mental State Examination score of 25-30, a Wechsler Memory Scale Logical Memory IIa (delayed recall) score of 6-18, and elevated brain amyloid levels on 18F-florbetapir positron emission tomography.

MEASUREMENTS: Study participants who received placebo were followed up with post-baseline safety measures. Assessments included review of concomitant medication and adverse events, the Columbia Suicide Severity Rating Scale, electrocardiograms, and neuroimaging (brain magnetic resonance imaging).

RESULTS: In total, 591 study participants (mean age [standard deviation] 71.9 [5.0] years) were assigned to and received placebo in the A4 study, and were followed up to 240 weeks. Participants were primarily White (93.9%) and from the United States (86.8%); 60.4% were women. The most common serious adverse events (incidence rate per 100 person-years) were pneumonia (incidence rate=0.4; 95% confidence interval=0.2-0.7) and atrial fibrillation (incidence rate=0.4; 95% confidence interval=0.2-0.7). The most common treatment-emergent adverse events were upper respiratory tract infection (incidence rate=10.9; 95% confidence interval=9.4-12.5), fall (incidence rate=7.7; 95% confidence interval=6.6-9.0), and nasopharyngitis (incidence rate=5.8; 95% confidence interval=4.8-6.9). The most common ischemia-related findings on magnetic resonance imaging were subcortical infarction (incidence rate=1.4; 95% confidence interval=1.0-2.0) and acute ischemia (incidence rate=0.6; 95% confidence interval=0.3-1.0). Emergent amyloid-related imaging abnormalities with hemosiderin deposition occurred in 32.8% of participants who received placebo; the primary factor associated with these events during the post-baseline period was the number of microhemorrhages at baseline (odds ratio=349.9; 95% confidence interval=247.6-494.4; adjusted p<0.001).

CONCLUSION: Safety findings in the placebo-treated group from the A4 study provide a robust characterization of expected safety in a clinical trial population with preclinical Alzheimer's disease. These results may provide context in planning future studies and safety evaluations during ongoing blinded studies in preclinical Alzheimer's disease.},
}

Humans
Aged
Female
Male
*Positron-Emission Tomography
Aged, 80 and over
*Aniline Compounds/therapeutic use/adverse effects
*Alzheimer Disease/drug therapy/diagnostic imaging
Brain/diagnostic imaging/metabolism
Ethylene Glycols
Double-Blind Method
Amyloid beta-Peptides/metabolism

@article {pmid39044493,
year = {2024},
author = {Papp, KV and Maruff, P and Rentz, DM and Donohue, MC and Liu, A and Aisen, PS and Sperling, RA},
title = {Change in Digital Cognitive Test Performance between Solanezumab and Placebo Groups in Preclinical Alzheimer's Disease: Secondary Analyses from the A4 Study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {846-856},
doi = {10.14283/jpad.2024.137},
pmid = {39044493},
issn = {2426-0266},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Female ; Male ; Aged ; *Neuropsychological Tests ; Positron-Emission Tomography ; Cognition/drug effects ; Double-Blind Method ; Longitudinal Studies ; Amyloid beta-Peptides/metabolism ; Aniline Compounds/therapeutic use ; },
abstract = {BACKGROUND: Primary results from the Anti-Amyloid in Asymptomatic Alzheimer's disease Study (A4) suggested no benefit of solanezumab on its primary cognitive outcome, a composite of paper and pencil tests (the Preclinical Alzheimer's Cognitive Composite; PACC).

OBJECTIVE: To determine whether change in cognitive performance, assessed using the Computerized Cognitive Composite (C3) summary score and C3 individual tests, differed between treatment groups over 240 weeks, differed based on baseline Aβ burden, and tracked with PACC decline.

DESIGN: Longitudinal analysis of cognitive change over 240 weeks on the C3 Summary Score and C3 individual tests between participants randomly assigned to solanezumab at a dose of up to 1600 mg intravenously every 4 weeks versus placebo.

SETTING: The A4 study took place at 67 sites in Australia, Canada, Japan and the United States.

PARTICIPANTS: Cognitively unimpaired older adults (n=1117, Mean Age=71.9, 60.7% female) with elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) at baseline (n=549 in the solanezumab group; n=568 in the placebo group).

MEASUREMENTS: Participants completed the C3 battery and PACC every 6 months. The C3 Summary Score combines the Cogstate Brief Battery (CBB)-One Card Learning, the Behavioral Pattern Separation (BPS) Test- Object- Lure Discrimination Index, and the Face Name Associative Memory Exam (FNAME)- Face-Name Matching.

RESULTS: Change on the C3 Summary Score was moderately correlated with change on the PACC (Spearman's corr=0.53, 95% CI: 0.49 to 0.57; p<0.001). At 240 weeks, mean change in the C3 Summary Score did not differ between groups; +0.24 in the solanezumab group and +0.27 in the placebo group (mean difference= -0.02; 95% CI: -0.13 to 0.08; p = 0.650). Lack of a treatment effect was similarly observed across most individual C3 tests. Performance on the C3 tests were influenced by level of amyloid burden, where higher levels were associated with worse performance.

CONCLUSION: This study provides corroborating evidence that solanezumab does not slow cognitive decline in preclinical AD as exhibited with a computerized cognitive assessment with some evidence that solanezumab may exacerbate cognition on select digital outcomes. This study also provides important information that amyloid related cognitive change manifests differently on individual C3 tests.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal, Humanized/therapeutic use
Female
Male
Aged
*Neuropsychological Tests
Positron-Emission Tomography
Cognition/drug effects
Double-Blind Method
Longitudinal Studies
Amyloid beta-Peptides/metabolism
Aniline Compounds/therapeutic use

@article {pmid39044492,
year = {2024},
author = {Amariglio, RE and Grill, JD and Rentz, DM and Marshall, GA and Donohue, MC and Liu, A and Aisen, PS and Sperling, RA},
title = {Longitudinal Trajectories of the Cognitive Function Index in the A4 Study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {838-845},
doi = {10.14283/jpad.2024.125},
pmid = {39044492},
issn = {2426-0266},
mesh = {Humans ; Male ; Female ; Aged ; *Alzheimer Disease/psychology/drug therapy ; Longitudinal Studies ; *Positron-Emission Tomography ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Cognition/physiology ; Cognitive Dysfunction ; Neuropsychological Tests ; Aniline Compounds ; Ethylene Glycols ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; },
abstract = {BACKGROUND: The Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) Study failed to show a treatment benefit with solanezumab, but the longitudinal consequences of elevated amyloid were observed in study participants with objective decline on the Preclinical Alzheimer Cognitive Composite (PACC) and subjective decline on the combined Cognitive Function Index (participant + study partner CFI), during the trial period.

OBJECTIVES: We sought to expand on previous findings by comparing longitudinal patterns of participant and study partner CFI separately and their associations with the PACC stratified by baseline amyloid tertile over the course of the A4 Study.

DESIGN: Cognitively unimpaired older adult participants and their study partners were independently administered the CFI at screen prior to amyloid PET disclosure and then at 3 subsequent visits (week 48, week 168, week 240) of the study. PACC collected at visits concurrent with CFI administration were also examined longitudinally.

SETTING: The A4 Study was conducted at 67 sites in Australia, Canada, Japan, and the United States.

PARTICIPANTS: 1,147 participants with elevated amyloid based on florbetapir PET were enrolled in the A4 Study and included in these analyses. 583 were on placebo and 564 were treated with solanezumab.

MEASUREMENTS: The PACC was used to assess objective cognitive performance and the CFI was used to assess change in everyday cognitive functioning by the participant and their study partner independently. Amyloid level was characterized by Centiloid tertiles (<46.1 CL, 46.1 to 77.2 CL, >77.2 CL). Participants were aware of their elevated amyloid status, but not their CL tertile, or specific level of amyloid. Longitudinal correlations between participant and study partner CFI and PACC were examined at all visits where assessments were available. The impact of baseline amyloid tertile on CFI and PACC associations was also examined.

RESULTS: Both participant and study partner CFI increased over the duration of the study indicating worsening cognitive functioning. Results did not differ by treatment group. The association between higher CFI and worse PACC for both for participant and study partner became progressively stronger over the course of the study. PACC had a significantly higher correlation with study partner CFI than with participant CFI by week 168. The stronger correlations between study partner CFI and PACC were driven by those in the highest amyloid tertile.

CONCLUSION: Both participant and study partner report captured subtle changes in everyday cognitive functioning for participants with biomarker confirmed and disclosed preclinical AD. Moreover, study partner report was most highly aligned with cognitive decline, particularly among those with the highest amyloid load.},
}

Humans
Male
Female
Aged
*Alzheimer Disease/psychology/drug therapy
Longitudinal Studies
*Positron-Emission Tomography
*Antibodies, Monoclonal, Humanized/therapeutic use
Cognition/physiology
Cognitive Dysfunction
Neuropsychological Tests
Aniline Compounds
Ethylene Glycols
Amyloid beta-Peptides/metabolism
Aged, 80 and over

@article {pmid39044491,
year = {2024},
author = {Molina-Henry, D and Langford, O and Donohue, MC and Raman, R and Aisen, P and Johnson, KA and Rissman, RA and Sperling, R},
title = {Relationship between Plasma P-Tau217 and Amyloid PET in Racial and Ethnic Underrepresented Groups (RE-URG) Compared with Non RE-URG in LEARN and A4.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {831-837},
doi = {10.14283/jpad.2024.124},
pmid = {39044491},
issn = {2426-0266},
mesh = {Humans ; *Positron-Emission Tomography ; Aged ; Female ; Male ; *tau Proteins/metabolism/blood ; *Alzheimer Disease/blood/metabolism/diagnostic imaging ; Aged, 80 and over ; Retrospective Studies ; Aniline Compounds ; Ethnicity ; Biomarkers/blood/metabolism ; Brain/diagnostic imaging/metabolism ; Racial Groups ; United States ; Canada ; Ethylene Glycols ; Amyloid beta-Peptides/metabolism/blood ; Phosphorylation ; },
abstract = {BACKGROUND: Individuals from diverse racial and ethnic groups are severely underrepresented in Alzheimer's disease trials in part due to disproportionate biomarker ineligibility. Evidence from recent studies support plasma phosphorylated tau 217 (P-tau217) as an early marker for brain Aβ pathology and a reliable marker in predicting elevated brain amyloid PET in cognitively unimpaired adults.

OBJECTIVES: To examine whether the relationship between P-tau217 and 18-F florbetapir PET standard uptake value ratios (SUVR) is influenced by race and ethnicity in the Anti-Amyloid treatment in Asymptomatic Alzheimer's disease (A4) preclinical AD studies.

DESIGN: We conducted a retrospective analysis of A4 clinical trial and the LEARN natural history companion study data to evaluate the relationship between baseline P-tau217 and PET SUVR concentration levels by race and ethnicity.

SETTING: The analysis was conducted on samples from participants enrolled across 65 study sites in the United States and Canada.

PARTICIPANTS: Cognitively unimpaired adults aged 65-85 enrolled at North American sites in the A4 preclinical AD trial, pre-dose, (N=1018), and the LEARN (N=480) study. Participants were grouped into 2 categories, racial and ethnic underrepresented group (RE-URG) and non-RE-URG (nRE-URG) based on self-identification.

MEASUREMENTS: A mixed-effects regression model was fit to determine differences in the relationship between P-tau217 and PET SUVR by race and ethnicity, adjusting for age, and APOE ε4 carrier status.

RESULTS: Results from the linear mixed-effects model support that there was no statistically significant effect of race and ethnicity on the relationship between P-tau217 and PET SUVR.

CONCLUSION: These findings suggest that the relationship between plasma P-tau217 and PET SUVR is the same across race and ethnicity. Future analyses should corroborate these findings in a larger sample and examine whether plasma P-tau217 reflects the differential amyloid prevalence previously reported for other biomarkers of amyloid.},
}

Humans
*Positron-Emission Tomography
Aged
Female
Male
*tau Proteins/metabolism/blood
*Alzheimer Disease/blood/metabolism/diagnostic imaging
Aged, 80 and over
Retrospective Studies
Aniline Compounds
Ethnicity
Biomarkers/blood/metabolism
Brain/diagnostic imaging/metabolism
Racial Groups
United States
Canada
Ethylene Glycols
Amyloid beta-Peptides/metabolism/blood
Phosphorylation

@article {pmid39044490,
year = {2024},
author = {Rissman, RA and Donohue, MC and Langford, O and Raman, R and Abdel-Latif, S and Yaari, R and Holdridge, KC and Sims, JR and Molina-Henry, D and Jimenez-Maggiora, G and Johnson, KA and Aisen, PS and Sperling, RA},
title = {Longitudinal Phospho-tau217 Predicts Amyloid Positron Emission Tomography in Asymptomatic Alzheimer's Disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {823-830},
doi = {10.14283/jpad.2024.134},
pmid = {39044490},
issn = {2426-0266},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/blood/diagnosis ; *Positron-Emission Tomography ; Aged ; *tau Proteins/blood ; Male ; Female ; *Biomarkers/blood ; Aged, 80 and over ; Longitudinal Studies ; Antibodies, Monoclonal, Humanized/therapeutic use ; Brain/diagnostic imaging/metabolism ; Amyloid beta-Peptides/blood/metabolism ; },
abstract = {BACKGROUND: Blood-based AD biomarkers such as plasma P-tau217 are increasingly used in clinical trials as a screening tool.

OBJECTIVES: To assess the utility of an electrochemiluminescence (ECL) immunoassay in predicting brain amyloid PET status in cognitively unimpaired individuals.

SETTING: Plasma samples collected at baseline, week 12, and week 240 or endpoint originated from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.

PARTICIPANTS: Both A4 and LEARN enrolled eligible cognitively unimpaired persons 65 to 85 years. Individuals with elevated brain amyloid PET levels were eligible for the A4 Study, while those without elevated brain amyloid PET levels were eligible for the LEARN Study.

INTERVENTION: Participants in the A4 Study received intravenous solanezumab (up to 1600 mg) or placebo every 4 weeks. The LEARN Study is an observational study without intervention.

MEASUREMENTS: Plasma P-tau217 concentration levels from A4 Study participants were measured using an ECL immunoassay. Receiver Operating Characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by ≥22 CL and ≥ 33 CL.

RESULTS: Receiver operating characteristic curve (ROC) analysis indicates high diagnostic value of P-tau217 in individuals with amyloid PET ≥ 20 (Area under the ROC (AUROC): 0.87) and ≥ 33 CL (AUROC: 0.89). Repeated testing with the placebo group taken 12 weeks apart (range: 68 to 143 days) and the LEARN participants taken between 1.4 and 1.75 years resulted in a strong positive correlation (Corr. 0.91 (0.90 to 0.92)).

CONCLUSION: An ECL immunoassay testing plasma P-tau217 accurately predicts amyloid PET positivity in cognitively unimpaired individuals. Our future analyses aim to determine if use of this assay may reduce the screening burden of preclinical individuals into anti-amyloid clinical trials.},
}

Humans
*Alzheimer Disease/diagnostic imaging/blood/diagnosis
*Positron-Emission Tomography
Aged
*tau Proteins/blood
Male
Female
*Biomarkers/blood
Aged, 80 and over
Longitudinal Studies
Antibodies, Monoclonal, Humanized/therapeutic use
Brain/diagnostic imaging/metabolism
Amyloid beta-Peptides/blood/metabolism

@article {pmid39044489,
year = {2024},
author = {Rentz, DM and Rosenberg, PB and Sperling, RA and Donohue, MC and Raman, R and Liu, A and Aisen, PS},
title = {Characterizing Clinical Progression in Cognitively Unimpaired Older Individuals with Brain Amyloid: Results from the A4 Study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {814-822},
doi = {10.14283/jpad.2024.123},
pmid = {39044489},
issn = {2426-0266},
mesh = {Humans ; *Disease Progression ; Aged ; *Alzheimer Disease ; Female ; Male ; Aged, 80 and over ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Positron-Emission Tomography ; Brain/diagnostic imaging ; Mental Status and Dementia Tests ; Cognition/physiology/drug effects ; Double-Blind Method ; Aniline Compounds ; Ethylene Glycols ; },
abstract = {BACKGROUND: Clinical Dementia Rating (CDR) global (CDR-G) and sum of box scores (CDR-SB) are commonly used as primary outcome variables to measure progression or treatment effects in symptomatic Alzheimer disease (AD) clinical trials.

OBJECTIVES: We sought to determine whether the CDR is sensitive to change in pre-symptomatic AD and whether there are specific CDR boxes that are dynamic during the multi-year Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) secondary prevention study.

DESIGN: All participants entered the study with a CDR-G of 0. Box scores were examined individually and as composites of cognition (memory, orientation and judgment /problem solving) and function (community affairs and home/ hobbies). A progression in box score was tabulated only when the change occurred at two consecutive visits.

SETTING: The A4 study took place at 67 sites in Australia, Canada, Japan and the United States.

PARTICIPANTS: 1,147 individuals, ages 65-85, were randomized to either placebo (n= 583) or solanezumab (n= 564). All participants received a baseline flobetapir PET scan, an annual CDR, and cognitive testing every 6 months with the Primary Alzheimer Cognitive Composite (PACC) over the course of 240 weeks.

MEASUREMENTS: Generalized estimating equations and generalized least square models were used to explore the modeled mean progression rate in the CDR-G, CDR-SB, individual CDR boxes, and CDR composite scores in the combined solanezumab and placebo groups. Models were refitted to explore the probability of CDR progression in centiloid tertiles of amyloid at baseline (< 46.1 CL, 46.1 to 77.2 CL, > 77.2 CL). All models included effects for age, education, APOEε4 carrier status, baseline amyloid with flobetapir PET, treatment, and time-by-treatment.

RESULTS: There were no statistical differences between the placebo or solanezumab groups in CDR-G, CDR-SB, specific CDR boxes or CDR composite scores over the course of the trial. Changes in judgment/ problem solving were present at baseline and persisted over time, but progression on the CDR memory box and the CDR cognitive composite quickly predominated. Community affairs and home/ hobbies showed little progression. Personal care remained stable. The probability of cognitive and functional progression in CDR boxes began either at the intermediate or advanced amyloid level (46.1 to 77.2 CL, > 77.2 CL), while amyloid at the lowest level (< 46.1 CL) showed relatively little CDR progression.

CONCLUSIONS: The findings suggest that the CDR memory box and the CDR cognitive composite progressed over 240 weeks and were associated with intermediate and advanced stages of amyloid at baseline. Functional changes in community affairs and home/hobbies were relatively stable. These finding suggest that specific CDR box score changes may help refine our measurement of expected treatment effects in future AD prevention trials.},
}

Humans
*Disease Progression
Aged
*Alzheimer Disease
Female
Male
Aged, 80 and over
*Antibodies, Monoclonal, Humanized/therapeutic use
*Positron-Emission Tomography
Brain/diagnostic imaging
Mental Status and Dementia Tests
Cognition/physiology/drug effects
Double-Blind Method
Aniline Compounds
Ethylene Glycols

@article {pmid39044488,
year = {2024},
author = {Sperling, RA and Donohue, MC and Rissman, RA and Johnson, KA and Rentz, DM and Grill, JD and Heidebrink, JL and Jenkins, C and Jimenez-Maggiora, G and Langford, O and Liu, A and Raman, R and Yaari, R and Holdridge, KC and Sims, JR and Aisen, PS},
title = {Amyloid and Tau Prediction of Cognitive and Functional Decline in Unimpaired Older Individuals: Longitudinal Data from the A4 and LEARN Studies.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {11},
number = {4},
pages = {802-813},
doi = {10.14283/jpad.2024.122},
pmid = {39044488},
issn = {2426-0266},
mesh = {Humans ; *Positron-Emission Tomography ; Female ; Aged ; Male ; *tau Proteins/blood ; Longitudinal Studies ; *Cognitive Dysfunction ; *Biomarkers/blood ; Alzheimer Disease/blood/diagnostic imaging/drug therapy ; Activities of Daily Living ; Antibodies, Monoclonal, Humanized/therapeutic use ; Amyloid beta-Peptides/blood/metabolism ; Aged, 80 and over ; Disease Progression ; Aniline Compounds ; },
abstract = {BACKGROUND: Converging evidence suggests that markers of Alzheimer's disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes.

OBJECTIVES: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay.

DESIGN: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aβ+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aβ-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks.

SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia.

PARTICIPANTS: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aβ+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aβ+ underwent tau PET imaging in A4 (n=350). Aβ- were enrolled into the LEARN Study (n=553).

MEASUREMENTS: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo).

RESULTS: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aβ- and A4 Aβ+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models.

CONCLUSIONS: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.},
}

Humans
*Positron-Emission Tomography
Female
Aged
Male
*tau Proteins/blood
Longitudinal Studies
*Cognitive Dysfunction
*Biomarkers/blood
Alzheimer Disease/blood/diagnostic imaging/drug therapy
Activities of Daily Living
Antibodies, Monoclonal, Humanized/therapeutic use
Amyloid beta-Peptides/blood/metabolism
Aged, 80 and over
Disease Progression
Aniline Compounds

@article {pmid39044310,
year = {2024},
author = {Hokett, E and Lao, P and Avila-Rieger, J and Turney, IC and Adkins-Jackson, PB and Johnson, DA and Davidson, P and Chen, R and Shechter, A and Osorio, RS and Brickman, AM and Palta, P and Manly, JJ},
title = {Interactions among neighborhood conditions, sleep quality, and episodic memory across the adult lifespan.},
journal = {Ethnicity & health},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/13557858.2024.2379116},
pmid = {39044310},
issn = {1465-3419},
abstract = {OBJECTIVES: On average, adults racialized as non-Hispanic Black and Hispanic sleep more poorly than adults racialized as non-Hispanic White (hereafter, Black, Hispanic, White), but associations between factors that may moderate sleep-memory associations in these groups, such as neighborhood conditions, are unclear. Poorer neighborhood conditions (e.g. lower neighborhood cohesion) may be negatively associated with sleep quality and multiplicatively influence sleep-memory associations. We hypothesized lower ratings of neighborhood conditions would be associated with poorer sleep quality and moderate the association between sleep quality and episodic memory, especially in Black and Hispanic adults, who are disproportionately situated in poor neighborhood conditions.

DESIGN: Seven-hundred-thirty-six adults across the adult lifespan (27-89 years) were recruited from the northern Manhattan community as a part of the Offspring Study of Racial and Ethnic Disparities in Alzheimer's disease. Sleep quality was assessed using a modified version of the Pittsburgh Sleep Quality Index, and episodic memory was evaluated with the Buschke Selective Reminding Test. With multiple regression models, we measured associations between perceived neighborhood conditions and sleep quality and the interaction between sleep quality and neighborhood conditions on episodic memory stratified by racial/ethnic and gender identity groups.

RESULTS: Overall, poorer neighborhood conditions were associated with poorer sleep quality. In Black and Hispanic women, the sleep-memory association was moderated by neighborhood conditions. With more favorable neighborhood conditions, Black women showed an association between higher sleep quality and higher memory performance, and Hispanic women showed a protective effect of neighborhood (higher memory even when sleep quality was poor).

CONCLUSION: Poorer neighborhood experiences may contribute to poorer sleep quality across groups. In Black and Hispanic women, the association between sleep quality and episodic memory performance was dependent upon neighborhood conditions. These findings may inform tailored, structural level sleep interventions, aimed to improve neighborhood experiences and thereby sleep quality and episodic memory.},
}

@article {pmid39044293,
year = {2024},
author = {Byeon, JH and Byun, MS and Yi, D and Jung, JH and Sohn, BK and Chang, YY and Kong, N and Jung, G and Ahn, H and Lee, JY and Lee, YS and Kim, YK and Lee, DY and , },
title = {Moderation of thyroid hormones for the relationship between amyloid and tau pathology.},
journal = {Alzheimer's research & therapy},
volume = {16},
number = {1},
pages = {164},
pmid = {39044293},
issn = {1758-9193},
support = {NRF-2014M3C7A1046042//Ministry of Science and ICT, Republic of Korea/ ; NRF-2014M3C7A1046042//Ministry of Science and ICT, Republic of Korea/ ; HI18C0630 & HI19C0149//Ministry of Health & Welfare, Republic of Korea/ ; HI18C0630 & HI19C0149//Ministry of Health & Welfare, Republic of Korea/ ; No. 3020200030//Seoul National University Hospital, Republic of Korea/ ; No. 3020200030//Seoul National University Hospital, Republic of Korea/ ; U01AG072177//National Institute of Aging, United States of America/ ; U01AG072177//National Institute of Aging, United States of America/ ; },
mesh = {Humans ; Male ; Female ; Aged ; *tau Proteins/blood/metabolism ; Cross-Sectional Studies ; *Positron-Emission Tomography ; *Thyroid Hormones/blood ; *Amyloid beta-Peptides/metabolism/blood ; Middle Aged ; Aged, 80 and over ; Brain/diagnostic imaging/metabolism/pathology ; Alzheimer Disease/blood/diagnostic imaging/metabolism/pathology ; Thyroxine/blood ; Thyrotropin/blood ; Cohort Studies ; },
abstract = {BACKGROUND: Altered thyroid hormone levels have been associated with increased risk of Alzheimer's disease (AD) dementia and related cognitive decline. However, the neuropathological substrates underlying the link between thyroid hormones and AD dementia are not yet fully understood. We first investigated the association between serum thyroid hormone levels and in vivo AD pathologies including both beta-amyloid (Aβ) and tau deposition measured by positron emission tomography (PET). Given the well-known relationship between Aβ and tau pathology in AD, we additionally examined the moderating effects of thyroid hormone levels on the association between Aβ and tau deposition.

METHODS: This cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. This study included a total of 291 cognitively normal adults aged 55 to 90. All participants received comprehensive clinical assessments, measurements for serum total triiodothyronine (T3), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), and brain imaging evaluations including [[11]C]-Pittsburgh compound B (PiB)- PET and [[18]F] AV-1451 PET.

RESULTS: No associations were found between either thyroid hormones or TSH and Aβ and tau deposition on PET. However, fT4 (p = 0.002) and fT3 (p = 0.001) exhibited significant interactions with Aβ on tau deposition: The sensitivity analyses conducted after the removal of an outlier showed that the interaction effect between fT4 and Aβ deposition was not significant, whereas the interaction between fT3 and Aβ deposition remained significant. However, further subgroup analyses demonstrated a more pronounced positive relationship between Aβ and tau in both the higher fT4 and fT3 groups compared to the lower group, irrespective of outlier removal. Meanwhile, neither T3 nor TSH had any interaction with Aβ on tau deposition.

CONCLUSION: Our findings suggest that serum thyroid hormones may moderate the relationship between cerebral Aβ and tau pathology. Higher levels of serum thyroid hormones could potentially accelerate the Aβ-dependent tau deposition in the brain. Further replication studies in independent samples are needed to verify the current results.},
}

Humans
Male
Female
Aged
*tau Proteins/blood/metabolism
Cross-Sectional Studies
*Positron-Emission Tomography
*Thyroid Hormones/blood
*Amyloid beta-Peptides/metabolism/blood
Middle Aged
Aged, 80 and over
Brain/diagnostic imaging/metabolism/pathology
Alzheimer Disease/blood/diagnostic imaging/metabolism/pathology
Thyroxine/blood
Thyrotropin/blood
Cohort Studies

@article {pmid39044290,
year = {2024},
author = {Kim, DY and Kim, SM and Han, IO},
title = {Chronic rapid eye movement sleep deprivation aggravates the pathogenesis of Alzheimer's disease by decreasing brain O-GlcNAc cycling in mice.},
journal = {Journal of neuroinflammation},
volume = {21},
number = {1},
pages = {180},
pmid = {39044290},
issn = {1742-2094},
support = {RS-2024-00346770//National Research Foundation of Korea/ ; Research Grant//Inha University/ ; },
mesh = {Animals ; Mice ; *Sleep Deprivation/metabolism/complications ; *Alzheimer Disease/metabolism/pathology ; *Brain/metabolism/pathology ; Male ; Mice, Inbred C57BL ; tau Proteins/metabolism ; Acetylglucosamine/metabolism ; N-Acetylglucosaminyltransferases/metabolism ; Sleep, REM/physiology ; Amyloid beta-Peptides/metabolism ; },
abstract = {This study investigated the role of O-GlcNAc cycling in Alzheimer's disease-related changes in brain pathophysiology induced by chronic REM sleep deprivation (CSD) in mice. CSD increased amyloid beta (Aβ) and p-Tau accumulation and impaired learning and memory (L/M) function. CSD decreased dendritic length and spine density. CSD also increased the intensity of postsynaptic density protein-95 (PSD-95) staining. All of these Alzheimer's disease (AD) pathogenic changes were effectively reversed through glucosamine (GlcN) treatment by enhancing O-GlcNAcylation. Interestingly, the lelvel of O-GlcNAcylated-Tau (O-Tau) exhibited an opposite trend compared to p-Tau, as it was elevated by CSD and suppressed by GlcN treatment. CSD increased neuroinflammation, as indicated by elevated levels of glial fibrillary acidic protein and IBA-1-positive glial cells in the brain, which were suppressed by GlcN treatment. CSD promoted the phosphorylation of GSK3β and led to an upregulation in the expression of endoplasmic reticulum (ER) stress regulatory proteins and genes. These alterations were effectively suppressed by GlcN treatment. Minocycline not only suppressed neuroinflammation induced by CSD, but it also rescued the decrease in O-GlcNAc levels caused by CSD. Minocycline also reduced AD neuropathy without affecting CSD-induced ER stress. Notably, overexpressing O-GlcNAc transferase in the dentate gyrus region of the mouse brain rescued CSD-induced cognitive dysfunction, neuropathy, neuroinflammation, and ER stress responses. Collectively, our findings reveal that dysregulation of O-GlcNAc cycling underlies CSD-induced AD pathology and demonstrate that restoration of OGlcNAcylation protects against CSD-induced neurodegeneration.},
}

Animals
Mice
*Sleep Deprivation/metabolism/complications
*Alzheimer Disease/metabolism/pathology
*Brain/metabolism/pathology
Male
Mice, Inbred C57BL
tau Proteins/metabolism
Acetylglucosamine/metabolism
N-Acetylglucosaminyltransferases/metabolism
Sleep, REM/physiology
Amyloid beta-Peptides/metabolism

@article {pmid39044289,
year = {2024},
author = {Reallon, E and Gervais, F and Moutet, C and Dauphinot, V and Desnavailles, P and Novais, T and Krolak-Salmon, P and Garnier-Crussard, A and Mouchoux, C and , },
title = {Impact of cumulative exposure to anticholinergic and sedative drugs on cognition in older adults: a memory clinic cohort study.},
journal = {Alzheimer's research & therapy},
volume = {16},
number = {1},
pages = {163},
pmid = {39044289},
issn = {1758-9193},
mesh = {Humans ; Male ; Female ; *Hypnotics and Sedatives/adverse effects ; Aged ; *Cholinergic Antagonists/adverse effects ; Cohort Studies ; *Cognitive Dysfunction/chemically induced/epidemiology ; Aged, 80 and over ; Cognition/drug effects ; Mental Status and Dementia Tests ; Longitudinal Studies ; France/epidemiology ; },
abstract = {BACKGROUND: Long-term exposure to anticholinergic and sedative drugs could be a modifiable risk factor for cognitive decline. The objective of this study was to measure the association between previous cumulative anticholinergic and sedative drug exposure (Drug Burden Index) and cognitive decline.

METHODS: A cohort study (MEMORA cohort) was conducted in a French memory clinic for patients attending a consultation between November 2014 and December 2020, with at least 2 Mini-Mental State Examination (MMSE) measurements (≥ 6 months apart) and available medication data from the local Primary Health Insurance Fund database (n = 1,970). Drug Burden Index was linearly cumulated until each MMSE measurement and was used to categorise patients according to their level of exposure (no exposure, moderate, or high). The longitudinal association between Drug Burden Index and MMSE was assessed using a multivariate linear mixed model, adjusted for age, education level, anxiety disorders, depressive disorders, functional autonomy, and behavioural disorders.

RESULTS: Overall, 1,970 patients were included with a mean follow-up duration of 2.78 years (± 1.54) and 2.99 visits per patients (5,900 MMSE + Drug Burden Index measurements collected). At baseline, 68.0% of patients had moderate cumulative anticholinergic and sedative drug exposure and a mean MMSE of 21.1. MMSE decrease was steeper in patients with moderate and high Drug Burden Index (-1.74 and -1.70/year, respectively) than in patients with no exposure (-1.26/year) after adjusting for age, education, anxiety and depressive disorders, functional autonomy, and behavioural disorders (p < 0.01).

CONCLUSIONS: Long-term exposure to anticholinergic and sedative drugs is associated with steeper cognitive decline. Medication review focusing on de-prescribing these drugs could be implemented early to reduce cognitive impairment.},
}

Humans
Male
Female
*Hypnotics and Sedatives/adverse effects
Aged
*Cholinergic Antagonists/adverse effects
Cohort Studies
*Cognitive Dysfunction/chemically induced/epidemiology
Aged, 80 and over
Cognition/drug effects
Mental Status and Dementia Tests
Longitudinal Studies
France/epidemiology

@article {pmid39044270,
year = {2024},
author = {Chen, M and Wang, C and Lin, Y and Chen, Y and Xie, W and Huang, X and Zhang, F and Fu, C and Zhuang, K and Zou, T and Can, D and Li, H and Wu, S and Luo, C and Zhang, J},
title = {Dorsal raphe nucleus-hippocampus serotonergic circuit underlies the depressive and cognitive impairments in 5×FAD male mice.},
journal = {Translational neurodegeneration},
volume = {13},
number = {1},
pages = {34},
pmid = {39044270},
issn = {2047-9158},
support = {92149303//National Natural Science Foundation of China/ ; 81925010//National Natural Science Foundation of China/ ; 91849205//National Natural Science Foundation of China/ ; U1905207//National Natural Science Foundation of China/ ; NV20230010//Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education/ ; NV20230014//Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education/ ; 2021YFS0385//Project of Sichuan Department of Science and Technology/ ; },
mesh = {Animals ; *Dorsal Raphe Nucleus/metabolism ; Male ; *Cognitive Dysfunction/genetics/metabolism/psychology/physiopathology ; Mice ; *Serotonergic Neurons/metabolism/physiology ; *Depression/metabolism/genetics/psychology ; *Mice, Transgenic ; *Disease Models, Animal ; *Alzheimer Disease/genetics/metabolism/psychology ; Hippocampus/metabolism ; Serotonin/metabolism ; Optogenetics ; Neural Pathways/metabolism/physiopathology ; },
abstract = {BACKGROUND: Depressive symptoms often occur in patients with Alzheimer's disease (AD) and exacerbate the pathogenesis of AD. However, the neural circuit mechanisms underlying the AD-associated depression remain unclear. The serotonergic system plays crucial roles in both AD and depression.

METHODS: We used a combination of in vivo trans-synaptic circuit-dissecting anatomical approaches, chemogenetic manipulations, optogenetic manipulations, pharmacological methods, behavioral testing, and electrophysiological recording to investigate dorsal raphe nucleus serotonergic circuit in AD-associated depression in AD mouse model.

RESULTS: We found that the activity of dorsal raphe nucleus serotonin neurons (DRN[5-HT]) and their projections to the dorsal hippocampal CA1 (dCA1) terminals (DRN[5-HT]-dCA1[CaMKII]) both decreased in brains of early 5×FAD mice. Chemogenetic or optogenetic activation of the DRN[5-HT]-dCA1[CaMKII] neural circuit attenuated the depressive symptoms and cognitive impairments in 5×FAD mice through serotonin receptor 1B (5-HT1BR) and 4 (5-HT4R). Pharmacological activation of 5-HT1BR or 5-HT4R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DRN[5-HT]-dCA1[CaMKII] neural circuit to improve synaptic plasticity.

CONCLUSIONS: These findings provide a new mechanistic connection between depression and AD and provide potential pharmaceutical prevention targets for AD.},
}

Animals
*Dorsal Raphe Nucleus/metabolism
Male
*Cognitive Dysfunction/genetics/metabolism/psychology/physiopathology
Mice
*Serotonergic Neurons/metabolism/physiology
*Depression/metabolism/genetics/psychology
*Mice, Transgenic
*Disease Models, Animal
*Alzheimer Disease/genetics/metabolism/psychology
Hippocampus/metabolism
Serotonin/metabolism
Optogenetics
Neural Pathways/metabolism/physiopathology

@article {pmid39044253,
year = {2024},
author = {Kim, S and Chun, H and Kim, Y and Kim, Y and Park, U and Chu, J and Bhalla, M and Choi, SH and Yousefian-Jazi, A and Kim, S and Hyeon, SJ and Kim, S and Kim, Y and Ju, YH and Lee, SE and Lee, H and Lee, K and Oh, SJ and Hwang, EM and Lee, J and Lee, CJ and Ryu, H},
title = {Astrocytic autophagy plasticity modulates Aβ clearance and cognitive function in Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {19},
number = {1},
pages = {55},
pmid = {39044253},
issn = {1750-1326},
support = {NRF-2020M3E5D9079742, NRF-2022R1A2C3013138//National Research Foundation (NRF)/ ; HU23C0217//National Research Foundation (NRF)/ ; 2E32901 and 2E32922//Korea Institute of Science and Technology/ ; 2E32901//Korea Institute of Science and Technology/ ; 2E33411//Korea Institute of Science and Technology/ ; IBS-R001-D2//Institute for Basic Science (IBS)/ ; R01NS109537//National Institute of Health (NIH)/ ; 2024-22-0131//Yonsei University/ ; NRF-2022R1A6A3A01086375//National Research Foundation of Korea/ ; NRF-2021R1C1C2095827//National Research Foundation of Korea (NRF)/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Animals ; *Autophagy/physiology ; *Astrocytes/metabolism ; *Amyloid beta-Peptides/metabolism ; Mice ; Humans ; *Mice, Transgenic ; Disease Models, Animal ; Cognition/physiology ; },
abstract = {BACKGROUND: Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer's disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of animal model of AD.

METHODS: Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aβ-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR).

RESULTS: Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Aβ aggregates in the brain of APP/PS1 mice. An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients.

CONCLUSIONS: Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.},
}

*Alzheimer Disease/metabolism/pathology
Animals
*Autophagy/physiology
*Astrocytes/metabolism
*Amyloid beta-Peptides/metabolism
Mice
Humans
*Mice, Transgenic
Disease Models, Animal
Cognition/physiology

@article {pmid39044102,
year = {2024},
author = {Hou, Y and Liu, F and Lin, N and Gao, S},
title = {Systematic review and meta-analysis of repetitive transcranial magnetic stimulation (rTMS) for activities of daily living in Alzheimer's disease.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {39044102},
issn = {1590-3478},
abstract = {OBJECTIVE: This systematic review of randomised controlled trials (RCTs) was conducted to assess the effect of repetitive transcranial magnetic stimulation (rTMS) on activities of daily living (ADLs) in Alzheimer's disease (AD) patients.

DATA SOURCES: Ten databases were retrieved for pertinent Chinese and English literatures published up until January 2024.

REVIEW METHODS: All RCTs of rTMS for ADLs in AD were included in this meta-analysis. Two researchers independently selected the literatures, retrieved the data of included literatures, accessed risk-of-bias of literatures with the Cochrane Collaboration's quality criteria and then cross-checked. Meta-analysis was carried out with Cochrane's Review Manager (RevMan, version 5.4). The PRISMA guidelines were followed in this systematic review.

RESULTS: The 37 literatures involving 2461 patients with AD were included in this study. Compared with the control groups received the interventions such as routine pharmacotherapy, cognitive training, ect., with/without sham-rTMS, the experiment groups received the interventions of the control groups and rTMS. The findings were as follows: ADL scale [mean difference (MD) = -3.92, 95%CI (-4.93, -2.91), P < 0.00001]; Barthel Index (BI) [MD = 9.75, 95% CI (6.66, 12.85), P < 0.00001]; Modified Barthel Index (MBI) [MD = 5.43, 95% CI (3.13, 7.73), P < 0.00001]. The differences were statistically significant for all indicators. In 29 studies, rTMS stimulation sites were located in the dorsolateral prefrontal cortex (DLPFC).

CONCLUSION: The rTMS could improve the ADLs in AD patients, and the DLPFC was a frequently used stimulation site of the rTMS for AD treatment.},
}

@article {pmid39044044,
year = {2024},
author = {Supti, ST and Koehn, LM and Newman, SA and Pan, Y and Nicolazzo, JA},
title = {Iron Reduces the Trafficking of Fatty Acids from Human Immortalised Brain Microvascular Endothelial Cells Through Modulation of Fatty Acid Transport Protein 1 (FATP1/SLC27A1).},
journal = {Pharmaceutical research},
volume = {},
number = {},
pages = {},
pmid = {39044044},
issn = {1573-904X},
abstract = {PURPOSE: Alzheimer's disease (AD) is associated with brain accumulation of amyloid-beta (Aβ) and neurofibrillary tangle formation, in addition to reduced brain docosahexaenoic acid (DHA) and increased brain iron levels. DHA requires access across the blood-brain barrier (BBB) to enter the brain, and iron has been shown to affect the expression and function of a number of BBB transporters. Therefore, this study aimed to assess the effect of iron on the expression and function of fatty acid binding protein 5 (FABP5) and fatty acid transport protein 1 (FATP1), both which mediate brain endothelial cell trafficking of DHA.

METHODS: The mRNA and protein levels of FABP5 and FATP1 in human cerebral microvascular endothelial (hCMEC/D3) cells was assessed by RT-qPCR and Western blot, respectively following ferric ammonium citrate (FAC) treatment (up to 750 µM, 72 h). The function of FABP5 and FATP1 was assessed via uptake and efflux of radiolabelled [3]H-oleic acid and [14]C-DHA.

RESULTS: FAC (500 µM, 72 h) had no impact on the expression of FABP5 at the protein and mRNA level in hCMEC/D3 cells, which was associated with a lack of effect on the uptake of [14]C-DHA. FAC led to a 19.7% reduction in FATP1 protein abundance in hCMEC/D3 cells with no impact on mRNA levels, and this was associated with up to a 32.6% reduction in efflux of [14]C-DHA.

CONCLUSIONS: These studies demonstrate a role of iron in down-regulating FATP1 protein abundance and function at the BBB, which may have implications on fatty acid access to the brain.},
}

@article {pmid39043843,
year = {2024},
author = {Kim, TA and Cruz, G and Syty, MD and Wang, F and Wang, X and Duan, A and Halterman, M and Xiong, Q and Palop, JJ and Ge, S},
title = {Neural circuit mechanisms underlying aberrantly prolonged functional hyperemia in young Alzheimer's disease mice.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {39043843},
issn = {1476-5578},
support = {R01AG066912//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG0821471//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P01AG073082//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Neurovascular defects are one of the most common alterations in Alzheimer's disease (AD) pathogenesis, but whether these deficits develop before the onset of amyloid beta (Aβ) accumulation remains to be determined. Using in vivo optical imaging in freely moving mice, we explored activity-induced hippocampal microvascular blood flow dynamics in App[SAA] knock-in and J20 mouse models of AD at early stages of disease progression. We found that prior to the onset of Aβ accumulation, there was a pathologically elevated blood flow response to context exploration, termed functional hyperemia. After the onset of Aβ accumulation, this context exploration-induced hyperemia declined rapidly relative to that in control mice. Using in vivo electrophysiology recordings to explore the neural circuit mechanism underlying this blood flow alteration, we found that hippocampal interneurons before the onset of Aβ accumulation were hyperactive during context exploration. Chemogenetic tests suggest that hyperactive activation of inhibitory neurons accounted for the elevated functional hyperemia. The suppression of nitric oxide (NO) produced from hippocampal interneurons in young AD mice decreased the accumulation of Aβ. Together, these findings reveal that neurovascular coupling is aberrantly elevated before Aβ deposition, and this hyperactive functional hyperemia declines rapidly upon Aβ accumulation.},
}

@article {pmid39043757,
year = {2024},
author = {Wong, PC and Abdullah, SS and Shapiai, MI},
title = {Exceptional performance with minimal data using a generative adversarial network for alzheimer's disease classification.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {17037},
pmid = {39043757},
issn = {2045-2322},
support = {Q.K130000.3843.22H18//Universiti Teknologi Malaysia/ ; Q.K130000.3843.22H18//Universiti Teknologi Malaysia/ ; Q.K130000.3843.22H18//Universiti Teknologi Malaysia/ ; },
mesh = {*Alzheimer Disease/classification/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; *Neural Networks, Computer ; Magnetic Resonance Imaging/methods ; Databases, Factual ; Male ; Female ; },
abstract = {The classification of Alzheimer's disease (AD) using deep learning models is hindered by the limited availability of data. Medical image datasets are scarce due to stringent regulations on patient privacy, preventing their widespread use in research. Moreover, although open-access databases such as the Open Access Series of Imaging Studies (OASIS) are available publicly for providing medical image data for research, they often suffer from imbalanced classes. Thus, to address the issue of insufficient data, this study proposes the integration of a generative adversarial network (GAN) that can achieve comparable accuracy with a reduced data requirement. GANs are unsupervised deep learning networks commonly used for data augmentation that generate high-quality synthetic data to overcome data scarcity. Experimental data from the OASIS database are used in this research to train the GAN model in generating synthetic MRI data before being included in a pretrained convolutional neural network (CNN) model for multistage AD classification. As a result, this study has demonstrated that a multistage AD classification accuracy above 80% can be achieved even with a reduced dataset. The exceptional performance of GANs positions them as a solution for overcoming the challenge of insufficient data in AD classification.},
}

*Alzheimer Disease/classification/diagnostic imaging/diagnosis
Humans
*Deep Learning
*Neural Networks, Computer
Magnetic Resonance Imaging/methods
Databases, Factual
Male
Female

@article {pmid39043619,
year = {2024},
author = {Hunt, T and Pontifex, MG and Vauzour, D},
title = {(Poly)phenols and brain health - beyond their antioxidant capacity.},
journal = {FEBS letters},
volume = {},
number = {},
pages = {},
doi = {10.1002/1873-3468.14988},
pmid = {39043619},
issn = {1873-3468},
abstract = {(Poly)phenols are a group of naturally occurring phytochemicals present in high amounts in plant food and beverages with various structures and activities. The impact of (poly)phenols on brain function has gained significant attention due to the growing interest in the potential benefits of these dietary bioactive molecules for cognitive health and neuroprotection. This review will therefore summarise the current knowledge related to the impact of (poly)phenols on brain health presenting evidence from both epidemiological and clinical studies. Cellular and molecular mechanisms in relation to the observed effects will also be described, including their impact on the gut microbiota through the modulation of the gut-brain axis. Although (poly)phenols have the potential to modulate the gut-brain axis regulation and influence cognitive function and decline through their interactions with gut microbiota, anti-inflammatory and antioxidant properties, further research, including randomised controlled trials and mechanistic studies, is needed to better understand the underlying mechanisms and establish causal relationships between (poly)phenol intake and brain health.},
}

@article {pmid39043346,
year = {2024},
author = {Valencia-Sanchez, S and Davis, M and Martensen, J and Hoeffer, C and Link, C and Opp, MR},
title = {Sleep-wake behavior and responses to sleep deprivation and immune challenge of protein kinase RNA-activated knockout mice.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bbi.2024.07.027},
pmid = {39043346},
issn = {1090-2139},
abstract = {Protein Kinase RNA-activated (PKR) is an enzyme that plays a role in many systemic processes, including modulation of inflammation, and is implicated in neurodegenerative diseases, such as Alzheimer's disease (AD). PKR phosphorylation results in the production of several cytokines involved in the regulation / modulation of sleep, including interleukin-1β, tumor necrosis factor-α and interferon-γ. We hypothesized targeting PKR would alter spontaneous sleep of mice, attenuate responses to sleep deprivation, and inhibit responses to immune challenge. To test these hypotheses, we determined the sleep-wake phenotype of mice lacking PKR (knockout; PKR[-/-]) during undisturbed baseline conditions; in responses to six hours of sleep deprivation; and after immune challenge with lipopolysaccharide (LPS). Adult male mice (C57BL/6J, n = 7; PKR[-/-], n = 7) were surgically instrumented with EEG recording electrodes and an intraperitoneal microchip to record core body temperature. During undisturbed baseline conditions, PKR [-/-] mice spent more time in non-rapid eye movement sleep (NREMS) and rapid-eye movement sleep (REMS), and less time awake at the beginning of the dark period of the light:dark cycle. Delta power during NREMS, a measure of sleep depth, was less in PKR[-/-] mice during the dark period, and core body temperatures were lower during the light period. Both mouse strains responded to sleep deprivation with increased NREMS and REMS, although these changes did not differ substantively between strains. The initial increase in delta power during NREMS after sleep deprivation was greater in PKR[-/-] mice, suggesting a faster buildup of sleep pressure with prolonged waking. Immune challenge with LPS increased NREMS and inhibited REMS to the same extent in both mouse strains, whereas the initial LPS-induced suppression of delta power during NREMS was greater in PKR[-/-] mice. Because sleep regulatory and immune responsive systems in brain are redundant and overlapping, other mediators and signaling pathways in addition to PKR are involved in the responses to acute sleep deprivation and LPS immune challenge.},
}

@article {pmid39043341,
year = {2024},
author = {Mackey-Alfonso, SE and Butler, MJ and Taylor, AM and Williams-Medina, AR and Muscat, SM and Fu, H and Barrientos, RM},
title = {Short-term high fat diet impairs memory, exacerbates the neuroimmune response, and evokes synaptic degradation via a complement-dependent mechanism in a mouse model of Alzheimer's disease.},
journal = {Brain, behavior, and immunity},
volume = {121},
number = {},
pages = {56-69},
doi = {10.1016/j.bbi.2024.07.021},
pmid = {39043341},
issn = {1090-2139},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disease characterized by profound memory impairments, synaptic loss, neuroinflammation, and hallmark pathological markers. High-fat diet (HFD) consumption increases the risk of developing AD even after controlling for metabolic syndrome, pointing to a role of the diet itself in increasing risk. In AD, the complement system, an arm of the immune system which normally tags redundant or damaged synapses for pruning, becomes pathologically overactivated leading to tagging of healthy synapses. While the unhealthy diet to AD link is strong, the underlying mechanisms are not well understood in part due to confounding variables associated with long-term HFD which can independently influence the brain. Therefore, we experimented with a short-term diet regimen to isolate the diet's impact on brain function without causing obesity. This project investigated the effect of short-term HFD on 1) memory, 2) neuroinflammation including complement, 3) AD pathology markers, 4) synaptic markers, and 5) in vitro microglial synaptic phagocytosis in the 3xTg-AD mouse model. Following the consumption of either standard chow or HFD, 3xTg-AD and non-Tg mice were tested for memory impairments. In a separate cohort of mice, levels of hippocampal inflammatory markers, complement proteins, AD pathology markers, and synaptic markers were measured. For the last set of experiments, BV2 microglial phagocytosis of synapses was evaluated. Synaptoneurosomes isolated from the hippocampus of 3xTg-AD mice fed chow or HFD were incubated with equal numbers of BV2 microglia. The number of BV2 microglia that phagocytosed synaptoneurosomes was tracked over time with a live-cell imaging assay. Finally, we incubated BV2 microglia with a complement receptor inhibitor (NIF) and repeated the assay. Behavioral analysis showed 3xTg-AD mice had significantly impaired long-term contextual and cued fear memory compared to non-Tg mice that was further impaired by HFD. HFD significantly increased inflammatory markers and complement expression while decreasing synaptic marker expression only in 3xTg-AD mice, without altering AD pathology markers. Synaptoneurosomes from HFD-fed 3xTg-AD mice were phagocytosed at a significantly higher rate than those from chow-fed mice, suggesting the synapses were altered by HFD. The complement receptor inhibitor blocked this effect in a dose-dependent manner, demonstrating the HFD-mediated increase in phagocytosis was complement dependent. This study indicates HFD consumption increases neuroinflammation and over-activates the complement cascade in 3xTg-AD mice, resulting in poorer memory. The in vitro data point to complement as a potential mechanistic culprit and therapeutic target underlying HFD's influence in increasing cognitive vulnerability to AD.},
}

@article {pmid39043267,
year = {2024},
author = {Wang, F and Chen, Z and Zhou, Q and Xie, L and Zheng, N and Chen, Z and Lin, J and Li, B and Li, L},
title = {Implications of Liquid-Liquid Phase Separation and Ferroptosis in Alzheimer's Disease.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110083},
doi = {10.1016/j.neuropharm.2024.110083},
pmid = {39043267},
issn = {1873-7064},
abstract = {Neuronal cell demise represents a prevalent occurrence throughout the advancement of Alzheimer's disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Its potential mechanisms include aggregation of soluble amyloid-beta (Aβ) to form insoluble amyloid plaques, abnormal phosphorylation of tau protein and formation of intracellular neurofibrillary tangles (NFTs), neuroinflammation, ferroptosis, oxidative stress, liquid-liquid phase separation (LLPS) and metal ion disorders. Among them, ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. The sensitivity to ferroptosis is tightly linked to numerous biological processes. Moreover, emerging evidences indicate that LLPS has great impacts on regulating human health and diseases, especially AD. Soluble Aβ can undergo LLPS to form liquid-like droplets, which can lead to the formation of insoluble amyloid plaques. Meanwhile, tau has a high propensity to condensate via the mechanism of LLPS, which can lead to the formation of NFTs. In this review, we summarize the most recent advancements pertaining to LLPS and ferroptosis in AD. Our primary focus is on expounding the influence of Aβ, tau protein, iron ions, and lipid oxidation on the intricate mechanisms underlying ferroptosis and LLPS within the domain of AD pathology. Additionally, we delve into the intricate cross-interactions that occur between LLPS and ferroptosis in the context of AD. Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for AD.},
}

@article {pmid39043156,
year = {2024},
author = {Boza-Calvo, C and Faustin, A and Zhang, Y and Briggs, AQ and Bernard, MA and Bubu, OM and Rao, JA and Gurin, L and Tall, SO and Osorio, RS and Marsh, K and Shao, Y and Masurkar, AV},
title = {Two-Year Longitudinal Outcomes of Subjective Cognitive Decline in Hispanics Compared to Non-hispanic Whites.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887241263097},
doi = {10.1177/08919887241263097},
pmid = {39043156},
issn = {0891-9887},
abstract = {BACKGROUND: Subjective cognitive decline (SCD), considered a preclinical dementia stage, is less understood in Hispanics, a high-risk group for dementia. We investigated SCD to mild cognitive impairment (MCI) progression risk, as well as baseline and longitudinal features of depressive symptoms, SCD complaints, and objective cognitive performance among Hispanics compared to non-Hispanic Whites (NHW).

METHODS: Hispanic (n = 23) and NHW (n = 165) SCD participants were evaluated at baseline and 2-year follow-up. Evaluations assessed function, depressive symptoms, SCD, and objective cognitive performance.

RESULTS: Hispanics were at increased risk of progression to MCI (OR: 6.10, 95% CI 1.09-34.20, P = .040). Hispanic participants endorsed more depressive symptoms at baseline (P = .048) that worsened more longitudinally (OR: 3.16, 95% CI 1.18-8.51, P = .023). Hispanic participants had increased SCD complaints on the Brief Cognitive Rating Scale (BCRS) (β = .40 SE: .17, P = .023), and in specific BCRS domains: concentration (β = .13, SE: .07, P = .047), past memory (β = .13, SE: .06, P = .039) and functional abilities (β = .10, SE: .05, P = .037). In objective cognitive performance, Hispanic ethnicity associated with decline in MMSE (β = -.27, SE: .13, P = .039), MoCA (β = -.80 SE: .34, P = .032), Trails A (β = 2.75, SE: .89, P = .002), Trails B (β = 9.18, SE: 2.71, P = .001) and Guild Paragraph Recall Delayed (β = -.80 SE: .28, P = .005). Conclusions: Hispanic ethnicity associated with a significantly increased risk of 2-year progression of SCD to MCI compared to NHW. This increased risk associated with increased depressive symptoms, distinctive SCD features, and elevated amnestic and non-amnestic objective cognitive decline. This supports further research to refine the assessment of preclinical dementia in this high-risk group.},
}

@article {pmid39042846,
year = {2024},
author = {Ingram, RU and Ocal, D and Halai, A and Pobric, G and Cash, DM and Crutch, S and Yong, KX and Lambon Ralph, MA},
title = {Graded Multidimensional Clinical and Radiologic Variation in Patients With Alzheimer Disease and Posterior Cortical Atrophy.},
journal = {Neurology},
volume = {103},
number = {4},
pages = {e209679},
doi = {10.1212/WNL.0000000000209679},
pmid = {39042846},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; Female ; Male ; *Atrophy/pathology ; Aged ; Cross-Sectional Studies ; Middle Aged ; *Magnetic Resonance Imaging ; *Neuropsychological Tests ; Cerebral Cortex/diagnostic imaging/pathology ; Cohort Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) spans heterogeneous typical and atypical phenotypes. Posterior cortical atrophy (PCA) is a striking example, characterized by prominent impairment in visual and other posterior functions in contrast to typical, amnestic AD. The primary study objective was to establish how the similarities and differences of cognition and brain volumes within AD and PCA (and by extension other AD variants) can be conceptualized as systematic variations across a transdiagnostic, graded multidimensional space.

METHODS: This was a cross-sectional, single-center, observational, cohort study performed at the National Hospital for Neurology & Neurosurgery, London, United Kingdom. Data were collected from a cohort of patients with PCA and AD, matched for age, disease duration, and Mini-Mental State Examination (MMSE) scores. There were 2 sets of outcome measures: (1) scores on a neuropsychological battery containing 22 tests spanning visuoperceptual and visuospatial processing, episodic memory, language, executive functions, calculation, and visuospatial processing and (2) measures extracted from high-resolution T1-weighted volumetric MRI scans. Principal component analysis was used to extract the transdiagnostic dimensions of phenotypical variation from the detailed neuropsychological data. Voxel-based morphometry was used to examine associations between the PCA-derived clinical phenotypes and the structural measures.

RESULTS: We enrolled 93 participants with PCA (mean: age = 59.9 years, MMSE = 21.2; 59/93 female) and 58 AD participants (mean: age = 57.1 years, MMSE = 19.7; 22/58 female). The principal component analysis for PCA (sample adequacy confirmed: Kaiser-Meyer-Olkin = 0.865) extracted 3 dimensions accounting for 61.0% of variance in patients' performance, reflecting general cognitive impairment, visuoperceptual deficits, and visuospatial impairments. Plotting AD cases into the PCA-derived multidimensional space, and vice versa, revealed graded, overlapping variations between cases along these dimensions, with no evidence for categorical-like patient clustering. Similarly, the relationship between brain volumes and scores on the extracted dimensions was overlapping for PCA and AD cases.

DISCUSSION: These results provide evidence supporting a reconceptualization of clinical and radiologic variation in these heterogenous AD phenotypes as being along shared phenotypic continua spanning PCA and AD, arising from systematic graded variations within a transdiagnostic, multidimensional neurocognitive geometry.},
}

Humans
*Alzheimer Disease/diagnostic imaging/pathology
Female
Male
*Atrophy/pathology
Aged
Cross-Sectional Studies
Middle Aged
*Magnetic Resonance Imaging
*Neuropsychological Tests
Cerebral Cortex/diagnostic imaging/pathology
Cohort Studies

@article {pmid39042667,
year = {2024},
author = {Rajani, RM and Ellingford, R and Hellmuth, M and Harris, SS and Taso, OS and Graykowski, D and Lam, FKW and Arber, C and Fertan, E and Danial, JSH and Swire, M and Lloyd, M and Giovannucci, TA and Bourdenx, M and Klenerman, D and Vassar, R and Wray, S and Sala Frigerio, C and Busche, MA},
title = {Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer's disease.},
journal = {PLoS biology},
volume = {22},
number = {7},
pages = {e3002727},
pmid = {39042667},
issn = {1545-7885},
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Animals ; *Oligodendroglia/metabolism ; *Amyloid beta-Peptides/metabolism ; Humans ; *Neurons/metabolism ; Mice ; *Mice, Transgenic ; *Disease Models, Animal ; Brain/metabolism/pathology ; Male ; Female ; Gene Knock-In Techniques ; },
abstract = {Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer's disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in the mouse model in vivo. Our findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Animals
*Oligodendroglia/metabolism
*Amyloid beta-Peptides/metabolism
Humans
*Neurons/metabolism
Mice
*Mice, Transgenic
*Disease Models, Animal
Brain/metabolism/pathology
Male
Female
Gene Knock-In Techniques

@article {pmid39042647,
year = {2024},
author = {Zhang, YL and Jia, SY and Yang, B and Miao, J and Su, C and Cui, ZG and Yang, LM and Guo, JH},
title = {Non-linear association of liver enzymes with cognitive performance in the elderly: A cross-sectional study.},
journal = {PloS one},
volume = {19},
number = {7},
pages = {e0306839},
pmid = {39042647},
issn = {1932-6203},
mesh = {Humans ; Male ; Female ; Cross-Sectional Studies ; Aged ; *Alanine Transaminase/blood/metabolism ; *Cognition/physiology ; *Alkaline Phosphatase/blood/metabolism ; *Liver/enzymology ; *gamma-Glutamyltransferase/blood/metabolism ; *Aspartate Aminotransferases/blood/metabolism ; Middle Aged ; Cognitive Dysfunction/blood ; Aged, 80 and over ; Nutrition Surveys ; },
abstract = {BACKGROUND: Although liver metabolic dysfunction has been found to potentially elevate susceptibility to cognitive impairment and dementia, there is still insufficient evidence to explore the non-linear association of liver enzymes with cognitive performance. Therefore, we aimed to elucidate the non-linear relationship between liver enzymes and cognitive performance.

METHODS: In this cross-sectional study, 2764 individuals aged ≥ 60 who participated in the National Health and Nutrition Survey (NHANES) between 2011 and 2014 were included. The primary data comprised liver enzyme levels (alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), AST/ALT ratio, and gamma-glutamyl transferase (GGT)), and cognitive performance was the major measured outcome. The associations were analyzed using weighted multivariate logistic regression, subgroup analysis, a generalized additive model, smooth fitting curves, and threshold effects.

RESULTS: The results of the fully adjusted model indicated that ALP was negatively associated with the animal fluency test (AFT) score (OR = 1.48, 95% CI: 1.11-1.98), whereas ALT demonstrated a positive association with the consortium to establish a registry for Alzheimer's disease (CERAD) test score (OR = 0.72, 95% CI: 0.53-0.97). Additionally, the AST/ALT ratio was negatively associated with the global cognitive test (OR = 2.39, 95% CI: 1.53-3.73), CERAD (OR = 2.61, 95% CI: 1.77-3.84), and digit symbol substitution test (DSST) scores (OR = 2.51, 95% CI: 1.57-4.02). GGT was also negatively associated with the AFT score (OR = 1.16, 95% CI: 1.01-1.33) in unadjusted model. A non-linear relationship was observed between liver enzymes and the risk of cognitive impairment as assessed by the global cognitive test. Specifically, when ALP > 60 U/L, 0.77 < AST/ALT < 1.76, and 25 < GGT < 94 U/L, higher liver enzyme levels were significantly associated with an elevated cognitive impairment risk, while a lower cognitive impairment risk when ALT level was > 17 U/L.

CONCLUSIONS: There is a non-linear relationship between liver enzymes and cognitive performance, indicating that liver enzyme levels should be maintained within a certain level to mitigate the risk of cognitive impairment.},
}

Humans
Male
Female
Cross-Sectional Studies
Aged
*Alanine Transaminase/blood/metabolism
*Cognition/physiology
*Alkaline Phosphatase/blood/metabolism
*Liver/enzymology
*gamma-Glutamyltransferase/blood/metabolism
*Aspartate Aminotransferases/blood/metabolism
Middle Aged
Cognitive Dysfunction/blood
Aged, 80 and over
Nutrition Surveys

@article {pmid39042528,
year = {2024},
author = {Zhou, H and He, L and Chen, BY and Shen, L and Zhang, Y},
title = {Multi-Modal Diagnosis of Alzheimer's Disease using Interpretable Graph Convolutional Networks.},
journal = {IEEE transactions on medical imaging},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TMI.2024.3432531},
pmid = {39042528},
issn = {1558-254X},
abstract = {The interconnection between brain regions in neurological disease encodes vital information for the advancement of biomarkers and diagnostics. Although graph convolutional networks are widely applied for discovering brain connection patterns that point to disease conditions, the potential of connection patterns that arise from multiple imaging modalities has yet to be fully realized. In this paper, we propose a multi-modal sparse interpretable GCN framework (SGCN) for the detection of Alzheimer's disease (AD) and its prodromal stage, known as mild cognitive impairment (MCI). In our experimentation, SGCN learned the sparse regional importance probability to find signature regions of interest (ROIs), and the connective importance probability to reveal disease-specific brain network connections. We evaluated SGCN on the Alzheimer's Disease Neuroimaging Initiative database with multi-modal brain images and demonstrated that the ROI features learned by SGCN were effective for enhancing AD status identification. The identified abnormalities were significantly correlated with AD-related clinical symptoms. We further interpreted the identified brain dysfunctions at the level of large-scale neural systems and sex-related connectivity abnormalities in AD/MCI. The salient ROIs and the prominent brain connectivity abnormalities interpreted by SGCN are considerably important for developing novel biomarkers. These findings contribute to a better understanding of the network-based disorder via multi-modal diagnosis and offer the potential for precision diagnostics. The source code is available at https://github.com/Houliang-Zhou/SGCN.},
}

@article {pmid39042243,
year = {2024},
author = {de Oliveira, GD and Vicente, LCC and Mourão, AM and Dos Santos, SHGP and de Lima Friche, AA and Bicalho, MAC},
title = {Dysphagia Screening in Brazilian Older Adults with Dementia: Content Development and Validation of a Questionnaire for Caregivers - RaDID-QC.},
journal = {Journal of cross-cultural gerontology},
volume = {},
number = {},
pages = {},
pmid = {39042243},
issn = {1573-0719},
support = {315133/2021-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; 309953/2018-9//Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; 09/2019//Edital PRPq - Programa Institucional de Auxílio à Pesquisa de Docentes Recém-Contratados./ ; 88887.569376/2020-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/ ; },
abstract = {This study aims to develop and validate the content and response processes of a questionnaire intended for caregivers to screen for dysphagia in Brazilian older adults with dementia due to Alzheimer's disease and/or vascular dementia. The instrument items were developed in Brazilian Portuguese language based on the theoretical framework. A committee of speech-language-hearing therapists analyzed the relevance, objectivity, clarity, and understandability of the items with the Delphi method. The content validity index cutoff agreement score for experts' answers to validate each item in the questionnaire was 0.78; in the intraclass correlation coefficient, it was 0.75 for all items. For response process validity evidence, the questionnaire was applied to 30 caregivers of older adults with dementia, who judged the clarity and understandability of the items. Each item was validated when understood by at least 95% of participants. The first version of the instrument had 29 items. After two expert assessments, the last version had 24 items. The intraclass correlation coefficient was 0.85. Only one item needed semantic adjustments in the pre-test. The dysphagia screening instrument applied to caregivers of older adults with dementia was developed with adequate content and response process validity evidence, enabling adjustments in its construct. Future studies will analyze the remaining evidence of validity and reliability.},
}

@article {pmid39042202,
year = {2024},
author = {de Paiva, IHR and da Silva, RS and Mendonça, IP and de Souza, JRB and Peixoto, CA},
title = {Semaglutide Attenuates Anxious and Depressive-Like Behaviors and Reverses the Cognitive Impairment in a Type 2 Diabetes Mellitus Mouse Model Via the Microbiota-Gut-Brain Axis.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {19},
number = {1},
pages = {36},
pmid = {39042202},
issn = {1557-1904},
support = {PROEP#400208/2019-9//Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz/ ; VPPCB-007-FIO-18-2-17//Fundação Oswaldo Cruz/ ; #301777/2012-8//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
mesh = {Animals ; *Glucagon-Like Peptides/pharmacology ; *Diabetes Mellitus, Type 2/complications/drug therapy/psychology/metabolism ; Mice ; *Cognitive Dysfunction/drug therapy/prevention & control/etiology/metabolism ; *Depression/drug therapy/psychology/metabolism ; Male ; *Anxiety/drug therapy/psychology/etiology ; *Gastrointestinal Microbiome/drug effects ; *Mice, Inbred C57BL ; *Brain-Gut Axis/drug effects ; Diabetes Mellitus, Experimental/complications/drug therapy/psychology/metabolism ; Disease Models, Animal ; Antidepressive Agents/pharmacology/therapeutic use ; },
abstract = {Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1β and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.},
}

Animals
*Glucagon-Like Peptides/pharmacology
*Diabetes Mellitus, Type 2/complications/drug therapy/psychology/metabolism
Mice
*Cognitive Dysfunction/drug therapy/prevention & control/etiology/metabolism
*Depression/drug therapy/psychology/metabolism
Male
*Anxiety/drug therapy/psychology/etiology
*Gastrointestinal Microbiome/drug effects
*Mice, Inbred C57BL
*Brain-Gut Axis/drug effects
Diabetes Mellitus, Experimental/complications/drug therapy/psychology/metabolism
Disease Models, Animal
Antidepressive Agents/pharmacology/therapeutic use

@article {pmid39041994,
year = {2024},
author = {Anandan, S and Rajendran, SS and Kumar, JP and Shajee, DS},
title = {Very Early Onset Familial Alzheimer's Disease Due to Mutation in PSEN1 I143T - First Case Report from South Asia.},
journal = {Neurology India},
volume = {72},
number = {3},
pages = {652-654},
doi = {10.4103/neurol-india.Neurol-India-D-24-00315},
pmid = {39041994},
issn = {1998-4022},
mesh = {Humans ; *Presenilin-1/genetics ; *Alzheimer Disease/genetics ; *Mutation ; Age of Onset ; Male ; Female ; Adult ; Asia, Southern ; },
}

Humans
*Presenilin-1/genetics
*Alzheimer Disease/genetics
*Mutation
Age of Onset
Male
Female
Adult
Asia, Southern

@article {pmid39041662,
year = {2024},
author = {Chen, H and Gao, X and Li, X and Yu, C and Liu, W and Qiu, J and Liu, W and Geng, H and Zheng, F and Gong, H and Xu, Z and Jia, J and Zhao, Q},
title = {Discovery of ZJCK-6-46: A Potent, Selective, and Orally Available Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor for the Treatment of Alzheimer's Disease.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.4c00483},
pmid = {39041662},
issn = {1520-4804},
abstract = {Targeting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been verified to regulate the progression of tau pathology as a promising treatment for Alzheimer's disease (AD), while the research progress on DYRK1A inhibitors seemed to be in a bottleneck period. In this work, we identified 32 (ZJCK-6-46) as the most potential DYRK1A inhibitor (IC50 = 0.68 nM) through rational design, systematic structural optimization, and comprehensive evaluation. Compound 32 exhibited acceptable in vitro absorption, distribution, metabolism, and excretion (ADME) properties and significantly reduced the expression of p-Tau Thr212 in Tau (P301L) 293T cells and SH-SY5Y cells. Moreover, compound 32 showed favorable bioavailability, blood-brain barrier (BBB) permeability, and the potential of ameliorating cognitive dysfunction by obviously reducing the expression of phosphorylated tau and neuronal loss in vivo, which was deserved as a valuable molecular tool to reveal the role of DYRK1A in the pathogenesis of AD and to further promote the development of anti-AD drugs.},
}

@article {pmid39041435,
year = {2024},
author = {Leuzy, A and Raket, LL and Villemagne, VL and Klein, G and Tonietto, M and Olafson, E and Baker, S and Saad, ZS and Bullich, S and Lopresti, B and Bohorquez, SS and Boada, M and Betthauser, TJ and Charil, A and Collins, EC and Collins, JA and Cullen, N and Gunn, RN and Higuchi, M and Hostetler, E and Hutchison, RM and Iaccarino, L and Insel, PS and Irizarry, MC and Jack, CR and Jagust, WJ and Johnson, KA and Johnson, SC and Karten, Y and Marquié, M and Mathotaarachchi, S and Mintun, MA and Ossenkoppele, R and Pappas, I and Petersen, RC and Rabinovici, GD and Rosa-Neto, P and Schwarz, CG and Smith, R and Stephens, AW and Whittington, A and Carrillo, MC and Pontecorvo, MJ and Haeberlein, SB and Dunn, B and Kolb, HC and Sivakumaran, S and Rowe, CC and Hansson, O and Doré, V},
title = {Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.13908},
pmid = {39041435},
issn = {1552-5279},
support = {//Food and Drug Administration (FDA) of the Department of Health and Human Services (HHS)/ ; 2022-00775//Swedish Research Council/ ; ERAPERMED2021-184//ERA PerMed/ ; 2017-0383//Knut and Alice Wallenberg foundation/ ; //Strategic Research Area MultiPark/ ; AF-980907//Swedish Alzheimer Foundation/ ; FO2021-0293//Swedish Brain Foundation/ ; 1412/22//The Parkinson foundation of Sweden/ ; //Cure Alzheimer's fund/ ; //Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse/ ; 2020-O000028//Skåne University Hospital Foundation/ ; 2022-1259//Regionalt Forskningsstöd/ ; 2022-Projekt0080//ALF agreement/ ; P30-AG062422//NIH/NIA/ ; U01 AG057195/AG/NIA NIH HHS/United States ; R35 AG072362/AG/NIA NIH HHS/United States ; ZEN-21-848216/ALZ/Alzheimer's Association/United States ; //American College of Radiology/ ; //Rainwater Charitable Foundation/ ; //Alliance for Therapeutics in Neurodegeneration/ ; },
abstract = {INTRODUCTION: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis.

METHODS: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale.

RESULTS: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach.

DISCUSSION: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification.

HIGHLIGHTS: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.},
}

@article {pmid39041391,
year = {2024},
author = {Wisch, JK and Gordon, BA and Barthélemy, NR and Horie, K and Henson, RL and He, Y and Flores, S and Benzinger, TLS and Morris, JC and Bateman, RJ and Ances, BM and Schindler, SE},
title = {Predicting continuous amyloid PET values with CSF tau phosphorylation occupancies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.14132},
pmid = {39041391},
issn = {1552-5279},
support = {R01AG070941//National Institutes of Health (NIH)/ ; RF1AG061900//Tracy Family SILQ Center/ ; R01NR012907//Tracy Family SILQ Center/ ; R01NR012657//Tracy Family SILQ Center/ ; R01NR014449//Tracy Family SILQ Center/ ; K01 AG053474/AG/NIA NIH HHS/United States ; Knight ADRC Developmental Projects (NRB) P30 AG066444//Tracy Family SILQ Center/ ; P01AG003991//Tracy Family SILQ Center/ ; P01AG026276//Tracy Family SILQ Center/ ; U19 AG032438/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; //the Paula and Rodger O. Riney Fund/ ; //the Daniel J Brennan MD Fund/ ; //Fred Simmons Olga Mohan Fund,/ ; //the Chuck Zuckerberg Initiative (CZI)/ ; },
abstract = {INTRODUCTION: Cerebrospinal fluid (CSF) tau phosphorylation at multiple sites is associated with cortical amyloid and other pathologic changes in Alzheimer's disease. These relationships can be non-linear. We used an artificial neural network to assess the ability of 10 different CSF tau phosphorylation sites to predict continuous amyloid positron emission tomography (PET) values.

METHODS: CSF tau phosphorylation occupancies at 10 sites (including pT181/T181, pT217/T217, pT231/T231 and pT205/T205) were measured by mass spectrometry in 346 individuals (57 cognitively impaired, 289 cognitively unimpaired). We generated synthetic amyloid PET scans using biomarkers and evaluated their performance.

RESULTS: Concentration of CSF pT217/T217 had low predictive error (average error: 13%), but also a low predictive range (ceiling 63 Centiloids). CSF pT231/T231 has slightly higher error (average error: 19%) but predicted through a greater range (87 Centiloids).

DISCUSSION: Tradeoffs exist in biomarker selection. Some phosphorylation sites offer greater concordance with amyloid PET at lower levels, while others perform better over a greater range.

HIGHLIGHTS: Novel pTau isoforms can predict cortical amyloid burden. pT217/T217 accurately predicts cortical amyloid burden in low-amyloid individuals. Traditional CSF biomarkers correspond with higher levels of amyloid.},
}

@article {pmid39041342,
year = {2024},
author = {Biswas, S and Chowdhury, T and Banerjee, S and Dutta, K and Das, AK and Das, D},
title = {Improving the Efficiency of Luminescent Zn(II)-Modified N-Doped GOQD Nanomaterials in Parkinson's Disease Treatment: A Theoretical Mechanistic Framework Exploring Doping Effect.},
journal = {Chemistry, an Asian journal},
volume = {},
number = {},
pages = {e202400629},
doi = {10.1002/asia.202400629},
pmid = {39041342},
issn = {1861-471X},
abstract = {Levodopa, a widely prescribed drug in Parkinson's disease treatment, stands as the foremost prodrug of dopamine. An affordable self-testing kit is utilized to monitor levodopa content in anti-parkinson drugs in human serum. A photoluminescent trinuclear Zn(II) complex [Zn3(L)2(κ1-OAc)2(κ2-OAc)2] has been synthesized, which cleaves into mononuclear ZC in aqueous solution. ZC was found to detect L-Dopa in Tris-HCl buffer, exhibiting a moderate decrease in PL-emission. The real-life utility of the ZC probe is limited, for its lower sensitivity (LOD 35.3 µM) and separation challenges. Therefore, an interface between homogeneous and heterogeneous supports has been explored, leading to the strategic development of NGOZC, where ZC was grafted onto NGOQD. This material enables naked- eye detection under both ambient and UV light with color change from bright cyan to green, followed by dark. The nitrogen doping effect was investigated by several comparative investigations involving the synthesis of ZC-grafted GOQD, leading to enhanced quenching performance. Steady-state and time-resolved fluorescence titration study, morphological analysis, and computational calculations have been performed to get insights into the sensing mechanism. To the best of our knowledge, this as-synthesized NGOZC (LOD 1.78 nM) represents a promising strategy and platform for applications in biosensors, especially for Parkinson's and Alzheimer's diseases.},
}

@article {pmid39041310,
year = {2024},
author = {Magana-Ramirez, CM and Irizarry-Martinez, G and Gillen, DL and Grill, JD},
title = {Reasons for undergoing amyloid imaging among diverse enrollees in the A4 study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.14077},
pmid = {39041310},
issn = {1552-5279},
support = {DGE-1839285//The National Science Foundation's Graduate Research Fellowship/ ; P30 AG066519/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Understanding attitudes toward participation among diverse preclinical Alzheimer's disease (AD) trial participants could yield insights to instruct future recruitment.

METHODS: Using data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study, we examined differences among mutually exclusive racial and ethnic groups in views and perceptions of amyloid imaging (VPAI), a measure of motivations to undergo amyloid biomarker testing in the setting of preclinical AD. We used linear regression to quantify differences at baseline.

RESULTS: Compared to non-Hispanic or Latino (NH) White participants, Hispanic or Latino (3.52 points, 95% confidence interval [CI]: [2.61, 4.42]); NH Asian (2.97 points, 95% CI: [1.71, 4.22]); and NH Black participants (2.79 points, 95% CI: [1.96, 3.63]) participants demonstrated higher levels of endorsement of the VPAI items at baseline.

DISCUSSION: Differences may exist among participants from differing ethnic and racial groups in motivations to undergo biomarker testing in the setting of a preclinical AD trial.

HIGHLIGHTS: Representative samples in AD clinical trials are vital to result in generalizability. We assessed motivations to undergo amyloid imaging in a preclinical AD trial. Racial and ethnic minority groups showed higher endorsement of VPAI items. Differences were driven by perceived risk, plan/prepare, and curiosity domains. Few observations among racial and ethnic groups changed after biomarker disclosure.},
}

@article {pmid39041170,
year = {2024},
author = {Wu, QY and Xu, XG and Zhang, QY and Huang, SH and Zhang, DL},
title = {[Analysis of current situation of outcome indicators in randomized controlled trials on traditional Chinese medicine in treatment of Alzheimer's disease].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {49},
number = {11},
pages = {3113-3124},
doi = {10.19540/j.cnki.cjcmm.20240218.501},
pmid = {39041170},
issn = {1001-5302},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Randomized Controlled Trials as Topic ; *Drugs, Chinese Herbal/therapeutic use ; *Medicine, Chinese Traditional ; Treatment Outcome ; Aged ; },
abstract = {This study aims to analyze the current situation of outcome indicators in randomized controlled trial(RCT) of traditional Chinese medicine(TCM) treatment for Alzheimer's disease(AD), so as to provide a reference for establishing a core indicator set in this field. The researchers systematically searched CNKI, Wanfang, VIP, Sino Med, EMbase, PubMed, Medline, and Cochrane Library. Independent screening of literature and extraction of information was conducted according to the inclusion and exclusion criteria. In addition, the Ro B 2. 0 tool was used for bias risk assessment. A total of 78 RCTs were included, involving 6 379 patients,with 122 kinds of outcome indicators. According to functional attributes, the outcome indicators could be categorized into seven groups:TCM diseases(3 kinds, 13 times), symptoms and signs(26 kinds, 196 times), physical and chemical tests(68 kinds, 149 times),qua-lity of life(1 kind, 2 times), long-term prognosis(2 kinds, 2 times), economic evaluation(0 kind), safety events(21 kinds,194 times), and other indicators(1 kind, 1 time). The results show that the literature evaluation of RCTs of TCM treatment for AD is generally risky, and there are some problems in the selection of outcome indicators, such as lack of TCM characteristics, insignificant distinction between primary and secondary outcome indicators, lack of long-term prognosis and economic evaluation indicators, and non-standard safety event reports. It is suggested that future researchers should establish a core indicator set for AD that highlights the characteristics of TCM and then work to improve the quality of clinical trials.},
}

*Alzheimer Disease/drug therapy
Humans
*Randomized Controlled Trials as Topic
*Drugs, Chinese Herbal/therapeutic use
*Medicine, Chinese Traditional
Treatment Outcome
Aged

@article {pmid39041098,
year = {2024},
author = {Wang, HP and Hu, YY and Lyu, YJ and Meng, ZP and Chen, YQ and Yang, J},
title = {[Effect of Hei Xiaoyaosan regulating p38MAPK/Beclin-1/Bcl-2 pathway on autophagy level in Alzheimer's disease model rats].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {49},
number = {12},
pages = {3348-3355},
doi = {10.19540/j.cnki.cjcmm.20240216.101},
pmid = {39041098},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Male ; Rats ; *Drugs, Chinese Herbal/administration & dosage/pharmacology ; *Autophagy/drug effects ; *p38 Mitogen-Activated Protein Kinases/metabolism/genetics ; *Beclin-1/metabolism/genetics ; *Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Rats, Wistar ; *Disease Models, Animal ; Humans ; Hippocampus/drug effects/metabolism ; Signal Transduction/drug effects ; },
abstract = {To explore the effect of Hei Xiaoyaosan on autophagy levels in Alzheimer's disease(AD). A total of 100 4-month-old Wistar male rats were randomly selected as a blank group, and 10 rats were taken as a sham operation group and injected with 1 μL of normal saline on both sides of the hippocampus. The other rats were injected with Aβ_(1-42) solution in the hippocampus to replicate the AD model. Fifty successfully modeled rats were selected and randomly divided into the model group, Aricatio group(0.5 mg·kg~(-1)), and high, medium, and low dose groups of Hei Xiaoyaosan(15.30, 7.65, and 3.82 g·kg~(-1)), with 10 rats in each group. The rats were administered by continuous gavage for 42 days. Morris water maze was used to detect the learning and memory ability of rats, and Hoechst staining was used to observe the pathological changes of nerve cells in the hippocampal CA1 region. The mRNA expression of p38MAPK, Beclin-1, and Bcl-2 was detected by RT-qPCR.Western blot was used to detect the expressions of p38MAPK, Beclin-1, Bcl-2, APP, and related proteins. The level of Aβ_(1-42) in the hippocampus was detected by ELISA, and the expression level of LC3Ⅱ in the hippocampus was detected by immunohistochemistry. The experimental results showed that compared with the blank group, the learning and memory ability of rats in the model group decreased(P<0.01). The nuclei in the CA1 region of the hippocampus showed blue bright spots and were closely arranged. The mRNA expression of p38MAPK was up-regulated, and the mRNA expressions of Beclin-1 and Bcl-2 were down-regulated(P<0.01). The expressions of p38MAPK, p-p38MAPK, and APP were increased, while those of Beclin-1, Bcl-2, and p-Bcl-2 were decreased(P<0.01). The expression of Aβ_(1-42) was increased(P<0.01). The relative expression of LC3Ⅱ decreased(P<0.01). Compared with the model group, the learning and memory ability of rats in each administration group was improved(P<0.05 or P<0.01). The nuclei in the CA1 region of the hippocampus gradually became clear, showing light blue. The mRNA expression of p38MAPK was down-regulated(P<0.01), and that of Beclin-1 and Bcl-2 was increased(P<0.05 or P<0.01). The expressions of p38MAPK, p-p38MAPK, and APP were down-regulated, while those of Beclin-1, Bcl-2, and p-Bcl-2 were up-regulated(P<0.05 or P<0.01). The expression of Aβ_(1-42) was decreased(P<0.01). The relative expression of LC3Ⅱ was increased(P<0.01). It can be concluded that Hei Xiaoyaosan can improve the cognitive ability of AD model rats, and its potential mechanism may be related to regulating the p38MAPK/Beclin-1/Bcl-2 signaling pathway, increasing the level of autophagy, and reducing the accumulation of Aβ_(1-42).},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/genetics
Male
Rats
*Drugs, Chinese Herbal/administration & dosage/pharmacology
*Autophagy/drug effects
*p38 Mitogen-Activated Protein Kinases/metabolism/genetics
*Beclin-1/metabolism/genetics
*Proto-Oncogene Proteins c-bcl-2/metabolism/genetics
*Rats, Wistar
*Disease Models, Animal
Humans
Hippocampus/drug effects/metabolism
Signal Transduction/drug effects

@article {pmid39040759,
year = {2024},
author = {Lewandowski, DA and Clarkson, M and Mohammed, A},
title = {Uncharted Territories: Dynamic Hip Screw Migration Into the Pelvis Requiring Laparotomy.},
journal = {Cureus},
volume = {16},
number = {6},
pages = {e62810},
pmid = {39040759},
issn = {2168-8184},
abstract = {Hip fractures are common in patients with poor bone quality and are seen to affect the elderly and frail population. We report a case of implant failure after fixing an unstable intertrochanteric fracture with a dynamic hip screw (DHS). The patient presented with a DHS that had migrated into the pelvis approximately six months after surgery. Plain radiographs showed migration of the DHS through the acetabulum and into the pelvis. Migration of DHS into the pelvis is an extremely rare complication and has only been reported a few times. A 71-year-old man presented with a fall and confusion. The patient reported having a fall but could not recall the exact events. Past medical history included Alzheimer's dementia, osteoporosis, left total hip replacement, right DHS, peripheral neuropathy, and recurrent falls. He had undergone reduction and fixation of a right intertrochanteric fracture with DHS implant via direct lateral approach six months before hospital admission. On examination, he had right-sided hip pain and was unable to straighten leg raise. His abdomen was soft and non-tender, with no distension or palpable masses. Neurovascular status was normal, and no signs of infection were detected. On the anteroposterior radiograph, the implant seemed to have migrated through the acetabulum and into the abdomen. A CT of the abdomen and pelvis was performed to identify any visceral injuries (negative) and for surgical planning. The patient underwent a midline laparotomy to remove the implant. Although the exact reason for the implant failure is unknown, the migration of an unbroken hip screw into the abdomen and pelvis requiring laparotomy has not been reported in literature.},
}

@article {pmid39040632,
year = {2024},
author = {Shim, JW and Hyacinth, HI and Gonzalez-Perez, O},
title = {Editorial: Current therapeutic approaches in Alzheimer's disease: the use of a second drug with anti-amyloid-beta and beyond.},
journal = {Frontiers in neuroscience},
volume = {18},
number = {},
pages = {1449365},
doi = {10.3389/fnins.2024.1449365},
pmid = {39040632},
issn = {1662-4548},
}

@article {pmid39040573,
year = {2024},
author = {Meyer, OL and Farias, ST and Whitmer, RA and Kanaya, AM and Harvey, D and Hinton, L and Tiet, QQ and Vuong, Q and Gavett, B and Park, VT},
title = {Vietnamese Insights into Cognitive Aging Program (VIP): Objectives, study design, and cohort description.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {10},
number = {3},
pages = {e12494},
pmid = {39040573},
issn = {2352-8737},
abstract = {INTRODUCTION: There is a dearth of research on cognitive aging and dementia in Asian Americans, particularly in Vietnamese Americans, the fourth largest Asian subgroup in the United States.

METHODS: The Vietnamese Insights into Cognitive Aging Program (VIP) investigates early life adversity and war-related trauma and their associations with cognitive health in a community-based sample of older Vietnamese Americans in Northern California (i.e., Sacramento and Santa Clara counties). Baseline measurements include a comprehensive neuropsychological battery, including measures of global cognition along with executive function, semantic memory, and episodic memory. Data also include measures of functioning, early life adversity and trauma exposure, and psychosocial and traditional cardiovascular disease risk factors. Cognitive assessments will be repeated twice over the course of the data collection period, approximately 12- and 24- months post-baseline. Blood samples collected during Wave 2 will be assayed for biochemical risk factors.

RESULTS: Baseline assessments were conducted from January 2022 to November 2023, with N = 548 Vietnamese Americans; mean age ± SD was 73 ± 5.31 years and 55% of participants were women. There were significant differences in social factors by site, with Santa Clara participants having higher education (some college or higher: Sacramento, ≈25%; Santa Clara: ≈48%) and marginally higher incomes compared to Sacramento participants. A higher percentage of Santa Clara participants reported speaking English well or very well (24%) compared to Sacramento participants (13%), although the majority of the entire sample (81%) reported speaking some to no English (response options: not at all; some/a little bit; well/very well).

DISCUSSION: This longitudinal study providea a unique opportunity to more fully delineate psychosocial factors that contribute to dementia disparities in diverse and under-engaged populations. Future work will examine cognition, the prevalence of mild cognitive impairment and dementia, and other health outcomes, while controlling for site differences in all analyses.

HIGHLIGHTS: Vietnamese Insights into Cognitive Aging Program (VIP) is a new study.VIP has detailed early life and health data on 548 older Vietnamese Americans.History of war and trauma may contribute to Alzheimer's disease and related dementias (ADRD)-related burden.VIP may provide insight into ADRD burden in other understudied groups.},
}

@article {pmid39040546,
year = {2024},
author = {Rentsch, P and Ganesan, K and Langdon, A and Konen, LM and Vissel, B},
title = {Toward the development of a sporadic model of Alzheimer's disease: comparing pathologies between humanized APP and the familial J20 mouse models.},
journal = {Frontiers in aging neuroscience},
volume = {16},
number = {},
pages = {1421900},
pmid = {39040546},
issn = {1663-4365},
abstract = {BACKGROUND: Finding successful therapies for individuals with Alzheimer's disease (AD) remains an ongoing challenge. One contributing factor is that the mouse models commonly used in preclinical research primarily mimic the familial form of AD, whereas the vast majority of human cases are sporadic. Accordingly, for a sporadic mouse model of AD, incorporating the multifactorial aspects of the disease is of utmost importance.

METHODS: In the current study, we exposed humanized Aβ knock-in mice (hAβ-KI) to weekly low-dose lipopolysaccharide (LPS) injections until 24 weeks of age and compared the development of AD pathologies to the familial AD mouse model known as the J20 mice.

RESULTS: At the early time point of 24 weeks, hAβ-KI mice and J20 mice exhibited spatial memory impairments in the Barnes maze. Strikingly, both hAβ-KI mice and J20 mice showed significant loss of dendritic spines when compared to WT controls, despite the absence of Aβ plaques in hAβ-KI mice at 24 weeks of age. Glial cell numbers remained unchanged in hAβ-KI mice compared to WT, and LPS exposure in hAβ-KI mice did not result in memory deficits and failed to exacerbate any other examined AD pathology.

CONCLUSION: The study highlights the potential of hAβ-KI mice as a model for sporadic AD, demonstrating early cognitive deficits and synaptic alterations despite no evidence of Aβ plaque formation. These findings underscore the importance of considering multifactorial influences in sporadic AD pathogenesis and the need for innovative models to advance our understanding and treatment strategies for this complex disease.},
}

@article {pmid39040486,
year = {2024},
author = {Honda Pazili, T},
title = {A Severe Alzheimer's Disease Patient Improved by Intravenous Mesenchymal Stem Cell Transplant.},
journal = {Case reports in neurological medicine},
volume = {2024},
number = {},
pages = {8353492},
pmid = {39040486},
issn = {2090-6668},
abstract = {Alzheimer's disease (AD) is a progressive neurological disorder and is the most common form of dementia. The terminal stage of AD is characterized by severe cognitive and substantial functional decline, requiring extensive assistance with daily activities. As effective therapies at this stage are not fully available, development of therapeutics that can recover any symptoms would be important to improve the quality of life. Recently, stem cell therapy has gathered a lot of attention in several neurological diseases, including AD. Here, we report an AD patient at the terminal stage whose symptoms were improved by the intravenous administration of ex vivo-expanded bone marrow-derived mesenchymal stem cells (MSC). The case is a 61-year-old woman with severe Alzheimer's disease who had been admitted to the special nursing home. She could neither walk nor sit up independently. She also did neither smile nor gaze properly when talked to. Rigidity including neck motion was observed. She was on dysphagia diets. We cultured her bone-marrow-derived MSCs and intravenously administered 1,5 × 10[8] cells. After the treatment, smile loss, eye movement dysfunction, and neck immobility were improved. This is the first case report that showed the therapeutic effects of MSCs on terminal symptoms of AD.},
}

@article {pmid39040474,
year = {2024},
author = {Soni, P and Ammal Kaidery, N and Sharma, SM and Gazaryan, I and Nikulin, SV and Hushpulian, DM and Thomas, B},
title = {A critical appraisal of ferroptosis in Alzheimer's and Parkinson's disease: new insights into emerging mechanisms and therapeutic targets.},
journal = {Frontiers in pharmacology},
volume = {15},
number = {},
pages = {1390798},
pmid = {39040474},
issn = {1663-9812},
support = {R01 NS101967/NS/NINDS NIH HHS/United States ; R01 NS133688/NS/NINDS NIH HHS/United States ; RF1 AG077396/AG/NIA NIH HHS/United States ; },
abstract = {Neurodegenerative diseases represent a pressing global health challenge, and the identification of novel mechanisms underlying their pathogenesis is of utmost importance. Ferroptosis, a non-apoptotic form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a pivotal player in the pathogenesis of neurodegenerative diseases. This review delves into the discovery of ferroptosis, the critical players involved, and their intricate role in the underlying mechanisms of neurodegeneration, with an emphasis on Alzheimer's and Parkinson's diseases. We critically appraise unsolved mechanistic links involved in the initiation and propagation of ferroptosis, such as a signaling cascade resulting in the de-repression of lipoxygenase translation and the role played by mitochondrial voltage-dependent anionic channels in iron homeostasis. Particular attention is given to the dual role of heme oxygenase in ferroptosis, which may be linked to the non-specific activity of P450 reductase in the endoplasmic reticulum. Despite the limited knowledge of ferroptosis initiation and progression in neurodegeneration, Nrf2/Bach1 target genes have emerged as crucial defenders in anti-ferroptotic pathways. The activation of Nrf2 and the inhibition of Bach1 can counteract ferroptosis and present a promising avenue for future therapeutic interventions targeting ferroptosis in neurodegenerative diseases.},
}

@article {pmid39040464,
year = {2024},
author = {Pina-Escudero, SD and La Joie, R and Spina, S and Hwang, JH and Miller, ZA and Huang, EJ and Grant, H and Mundada, NS and Boxer, AL and Gorno-Tempini, ML and Rosen, HJ and Kramer, JH and Miller, BL and Seeley, WW and Rabinovici, GD and Grinberg, LT},
title = {Comorbid neuropathology and atypical presentation of Alzheimer's disease.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {16},
number = {3},
pages = {e12602},
pmid = {39040464},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) neuropathological changes present with amnestic and nonamnestic (atypical) syndromes. The contribution of comorbid neuropathology as a substratum of atypical expression of AD remains under investigated.

METHODS: We examined whether atypical AD exhibited increased comorbid neuropathology compared to typical AD and if such neuropathologies contributed to the accelerated clinical decline in atypical AD.

RESULTS: We examined 60 atypical and 101 typical AD clinicopathological cases. The number of comorbid pathologies was similar between the groups (p = 0.09). Argyrophilic grain disease was associated with atypical presentation (p = 0.008) after accounting for sex, age of onset, and disease duration. Vascular brain injury was more common in typical AD (p = 0.022). Atypical cases had a steeper Mini-Mental Status Examination (MMSE) decline over time (p = 0.033).

DISCUSSION: Comorbid neuropathological changes are unlikely to contribute to atypical AD presentation and the steeper cognitive decline seen in this cohort.

HIGHLIGHTS: Autopsy cohort of 60 atypical and 101 typical AD; does comorbid pathology explain atypical presentation?Atypical versus Typical AD: No significant differences in comorbid neuropathologies were found (p = 0.09).Argyrophilic Grain Disease Association: significantly correlates with atypical AD presentations, suggesting a unique neuropathological pattern (p = 0.008).Vascular Brain Injury Prevalence: Vascular brain injury is more common in typical AD than in atypical AD (p = 0.022).Cognitive Decline in Atypical AD: Atypical AD patients experience a steeper cognitive decline measured by MMSE than those with typical AD despite lacking more comorbid neuropathology, highlighting the severity of atypical AD pathogenesis (p = 0.033).},
}

@article {pmid39040287,
year = {2024},
author = {Liu, L and Tang, L and Wang, Y and Liu, S and Zhang, Y},
title = {Expression of ITPR2 regulated by lncRNA-NONMMUT020270.2 in LPS-stimulated HT22 cells.},
journal = {Heliyon},
volume = {10},
number = {13},
pages = {e33491},
pmid = {39040287},
issn = {2405-8440},
abstract = {BACKGROUND: Long non-coding RNA (lncRNA)-NONMMUT020270.2 is downregulated and co-expressed with inositol 1,4,5-trisphosphate receptor type 2 (ITPR2) in the hippocampus of Alzheimer's disease (AD) mice. However, whether the expression of ITPR2 was regulated by lncRNA-NONMMUT020270.2 remains unclear. we aimed to investigate regulating relationship of lncRNA-NONMMUT020270.2 and ITPR2.

METHODS: HT22 cells were firstly transfected with the pcDNA3.1-lncRNA-NONMMUT020270.2 overexpression plasmid or with the lncRNA-NONMMUT020270.2 smart silencer, and then were stimulated with lipopolysaccharide (LPS) for 24h. The mRNA expression levels of lncRNA-NONMMUT020270.2 and ITPR2 were measured by reverse transcription-quantitative PCR. Cell viability was assessed using a Cell Counting Kit 8 assay. The expression of Aβ1-42 was detected by ELISA. The expression levels of p-tau, caspase-1, and inositol trisphosphate receptor (IP3R) proteins were detected by western-blotting. Nuclear morphological changes were detected by Hoechst staining. Flow cytometry and Fluo-3/AM were carried out to determine cell apoptosis and the intracellular Ca[2+].

RESULTS: LPS significantly decreased cell viability, and ITPR2 mRNA and IP3R protein expression levels. While it markedly enhanced the expression levels of p-tau and Aβ1-42, cell apoptosis rate, as well as intracellular Ca[2+] concentration (P < 0.05). In addition, lncRNA-NONMMUT020270.2 overexpression significantly increased the expressions levels of ITPR2 mRNA and IP3R protein (P < 0.05), and inhibited expression of p-tau and Aβ1-42, cell apoptosis rate, and reduced intracellular Ca[2+] concentration (P < 0.05). By contrast, lncRNA-NONMMUT020270.2 silencing notably downregulated expressions levels of ITPR2 mRNA and IP3R protein (P < 0.05), and elevated expression levels of p-tau and Aβ1-42, cell apoptosis rate, and intracellular Ca[2+] concentration (P < 0.05).

CONCLUSION: lncRNA-NONMMUT020270.2 was positively correlated with ITPR2 expression in LPS-induced cell. Downregulating the lncRNA-NONMMUT020270.2 and ITPR2 may promote cell apoptosis and increase intracellular Ca[2+] concentration.},
}

@article {pmid39040206,
year = {2024},
author = {Meng, W and Xu, J and Huang, Y and Wang, C and Song, Q and Ma, A and Song, L and Bian, J and Ma, Q and Yin, R},
title = {Autoencoder to Identify Sex-Specific Sub-phenotypes in Alzheimer's Disease Progression Using Longitudinal Electronic Health Records.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.07.24310055},
pmid = {39040206},
abstract = {Alzheimer's Disease (AD) is a complex neurodegenerative disorder significantly influenced by sex differences, with approximately two-thirds of AD patients being women. Characterizing the sex-specific AD progression and identifying its progression trajectory is a crucial step to developing effective risk stratification and prevention strategies. In this study, we developed an autoencoder to uncover sex-specific sub-phenotypes in AD progression leveraging longitudinal electronic health record (EHR) data from OneFlorida+ Clinical Research Consortium. Specifically, we first constructed temporal patient representation using longitudinal EHRs from a sex-stratified AD cohort. We used a long short-term memory (LSTM)-based autoencoder to extract and generate latent representation embeddings from sequential clinical records of patients. We then applied hierarchical agglomerative clustering to the learned representations, grouping patients based on their progression sub-phenotypes. The experimental results show we successfully identified five primary sex-based AD sub-phenotypes with corresponding progression pathways with high confidence. These sex-specific sub-phenotypes not only illustrated distinct AD progression patterns but also revealed differences in clinical characteristics and comorbidities between females and males in AD development. These findings could provide valuable insights for advancing personalized AD intervention and treatment strategies.},
}

@article {pmid39040205,
year = {2024},
author = {Dybing, KM and McAllister, TW and Wu, YC and McDonald, BC and Broglio, SP and Mihalik, JP and Guskiewicz, KM and Goldman, JT and Jackson, JC and Risacher, SL and Saykin, AJ and Nudelman, KNH},
title = {Association of Alzheimer's disease polygenic risk score with concussion severity and recovery metrics.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.10.24309042},
pmid = {39040205},
abstract = {Identification of genetic alleles associated with both Alzheimer's disease (AD) and concussion severity/recovery could help explain the association between concussion and elevated dementia risk. However, there has been little investigation into whether AD risk genes associate with concussion severity/recovery, and the limited findings are mixed. We used AD polygenic risk scores (PRS) and APOE genotypes to investigate any such associations in the NCAA-DoD Grand Alliance CARE Consortium (CARE) dataset. We assessed six outcomes in 931 total participants. The outcomes were two concussion recovery measures (number of days to asymptomatic status, number of days to return to play (RTP)) and four concussion severity measures (scores on SAC and BESS, SCAT symptom severity, and total number of symptoms). We calculated PRS using a published score [1] and performed multiple linear regression (MLR) to assess the relationship of PRS with the outcomes. We also used t-tests and chi-square tests to examine outcomes by APOE genotype, and MLR to analyze outcomes in European and African genetic ancestry subgroups. Higher PRS was associated with longer injury to RTP in the normal RTP (<24 days) subgroup (p = 0.024), and one standard deviation increase in PRS resulted in a 9.89 hour increase to the RTP interval. There were no other consistently significant effects, suggesting that high AD genetic risk is not strongly associated with more severe concussions or poor recovery in young adults. Future studies should attempt to replicate these findings in larger samples with longer follow-up using PRS calculated from diverse populations.},
}

@article {pmid39040183,
year = {2024},
author = {Chatterjee, A and Cavaillès, C and Davies, NM and Yaffe, K and Andrews, SJ},
title = {Disentangling the causal effects of education and participation bias on Alzheimer's disease using Mendelian Randomization.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.09.24310096},
pmid = {39040183},
abstract = {INTRODUCTION: People with university degrees have a lower incidence of Alzheimer's Disease (AD). However, the relationship between education and AD could be due to selection, collider, and ascertainment biases, such as lower familiarity with cognitive testing or the fact that those with degrees are more likely to participate in research. Here, we use two-sample Mendelian randomization (MR) to investigate the causal relationships between education, participation, and AD.

METHOD: We used genome-wide association study (GWAS) summary statistics for educational attainment, three different measures of participation, AD (clinically diagnosed AD), and AD/ADRD (clinical diagnosis and family history of AD and related dementias). Independent genome-wide significant single nucleotide polymorphisms (SNPs) were extracted from the exposure summary statistics and harmonized with the outcome SNPs. Fixed-effects inverse variance weighted meta-analysis was the primary MR method; Cochran's Q statistic and MR Egger intercept were used to test for heterogeneity and pleiotropy, and Radial-MR was used to identify outliers. Sensitivity analyses included MR Egger, Weighted Median, and Weighted mode. Bidirectional analyses were used to test if AD pathology affects participation and multivariable MR (MVMR) assessed independent exposure-outcome effects.

RESULTS: Educational attainment reduced the risk of AD (OR IVW 95% CI= 0.70 [0.63, 0.79], p = 8e-10), and the results were robust based on sensitivity analyses. However, education increased the risk of AD/ADRD, though the results were not robust to sensitivity analyses (OR IVW 95% CI= 1.09 [1.02, 1.15], p = 0.006). Participation in MHQ reduced the odds of AD (OR IVW 95% CI= 0.325 [0.128, 0.326], p = 0.01). When adjusting for participation in MVMR, education remained associated with a reduced risk of AD (OR IVW 95% CI= 0.76 [0.62, 0.92], p = 0.006).

CONCLUSION: Univariate MR analyses indicated that education and participation reduced the risk of AD. However, MR also suggested that education increased the risk of AD/ADRD, highlighting the inconsistencies between clinical and proxy diagnoses of AD, as proxy-AD may be affected by selection, collider, or ascertainment bias. MVMR indicated that participation is unlikely to explain the effect of education on AD identified in MR, and the protective effect of educational attainment may be due to other biological mechanisms, such as cognitive reserve.},
}

@article {pmid39040178,
year = {2024},
author = {Bernard, MA and Boutajangout, A and Debure, L and Ahmed, W and Briggs, AQ and Boza-Calvo, C and Vedvyas, A and Marsh, K and Bubu, OM and Osorio, RS and Wisniewski, T and Masurkar, AV},
title = {The relationship between anxiety and levels of Alzheimer's disease plasma biomarkers.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.09.24310168},
pmid = {39040178},
abstract = {Anxiety is highly prevalent in Alzheimer's disease (AD), correlating with CSF/PET biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/Aβ42 ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration.},
}

@article {pmid39040175,
year = {2024},
author = {Li, Y and Kronenberg, F and Coassin, S and Vardarajan, B and Reyes-Soffer, G},
title = {Ancestry specific distribution of LPA Kringle IV-Type-2 genetic variants highlight associations to apo(a) copy number, glucose, and hypertension.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.07.09.24310176},
pmid = {39040175},
abstract = {BACKGROUND: High Lp(a) levels contribute to atherosclerotic cardiovascular disease and are tightly regulated by the LPA gene. Lp(a) levels have an inverse correlation with LPA Kringle IV Type-2 (KIV-2) copy number (CN). Black (B) and Hispanic (H) individuals exhibit higher levels of Lp(a), and rates of CVD compared to non-Hispanic Whites (NHW). Therefore, we investigated genetic variations in the LPA KIV-2 region across three ancestries and their associations with metabolic risk factors.

METHODS: Using published pipelines, we analyzed a multi-ethnic whole exome dataset comprising 3,817 participants from the Washington Heights and Inwood Columbia Aging Project (WHICAP): 886 [NHW (23%), 1,811 Caribbean (C) H (47%), and 1,120 B individuals (29%). Rare and common variants (alternative allele carrier frequency, CF < 0.01 or > 0.99 and 0.01 < CF < 0.99, respectively) were identified and KIV-2 CN estimated. The associations of variants and CN with history of heart disease, hypertension (HTN), stroke, lipid levels and clinical diagnosis of Alzheimer's disease (AD) was assessed. A small pilot provided in-silico validation of study findings.

RESULTS: We report 1421 variants in the LPA KIV-2 repeat region, comprising 267 exonic and 1154 intronic variants. 61.4% of the exonic variants have not been previously described. Three novel exonic variants significantly increase the risk of HTN across all ethnic groups: 4785-C/A (frequency = 78%, odds ratio [OR] = 1.45, p = 0.032), 727-T/C (frequency = 96%, OR = 2.11, p = 0.032), and 723-A/G (frequency = 96%, OR = 1.97, p = 0.038). Additionally, six intronic variants showed associations with HTN: 166-G/A, 387-G/C, 402-G/A, 4527-A/T, 4541-G/A, and 4653-A/T. One intronic variant, 412-C/T, was associated with decreased blood glucose levels (frequency = 72%, β = -14.52, p = 0.02). Three of the associations were not affected after adjusting for LPA KIV-2 CN: 412-C/T (β = -14.2, p = 0.03), 166-G/A (OR = 1.41, p = 0.05), and 387-G/C (OR = 1.40, p = 0.05). KIV CN itself was significantly associated with 314 variants and was negatively correlated with plasma total cholesterol levels.

CONCLUSIONS: In three ancestry groups, we identify novel rare and common LPA KIV-2 region variants. We report new associations of variants with HTN and Glucose levels. These results underscore the genetic complexity of the LPA KIV-2 region in influencing cardiovascular and metabolic health, suggesting potential genetic regulation of pathways that can be studied for research and therapeutic interventions.

CLINICAL PERSPECTIVE: Lp(a) levels are mostly controlled by the LPA gene and are higher in Blacks and Hispanics. Novel LPA KIV-2 variants found in three ancestry groups, including data on Caribbean Hispanics, show strong positive associations to hypertension and negative associations to glucose levels. Further characterization of these variants and identifying links to disease can help precision medicine efforts to understand disease mechanisms in all populations.},
}

@article {pmid39040111,
year = {2024},
author = {Liao, Z and Zhang, Q and Ren, N and Zhao, H and Zheng, X},
title = {Progress in mitochondrial and omics studies in Alzheimer's disease research: from molecular mechanisms to therapeutic interventions.},
journal = {Frontiers in immunology},
volume = {15},
number = {},
pages = {1418939},
pmid = {39040111},
issn = {1664-3224},
mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; *Mitochondria/metabolism ; Animals ; Genomics/methods ; Energy Metabolism ; Proteomics/methods ; },
abstract = {Alzheimer's disease (Alzheimer's disease, AD) is a progressive neurological disorder characterized by memory loss and cognitive impairment. It is characterized by the formation of tau protein neurofibrillary tangles and β-amyloid plaques. Recent studies have found that mitochondria in neuronal cells of AD patients exhibit various dysfunctions, including reduced numbers, ultrastructural changes, reduced enzyme activity, and abnormal kinetics. These abnormal mitochondria not only lead to the loss of normal neuronal cell function, but are also a major driver of AD progression. In this review, we will focus on the advances of mitochondria and their multi-omics in AD research, with particular emphasis on how mitochondrial dysfunction in AD drives disease progression. At the same time, we will focus on summarizing how mitochondrial genomics technologies have revealed specific details of these dysfunctions and how therapeutic strategies targeting mitochondria may provide new directions for future AD treatments. By delving into the key mechanisms of mitochondria in AD related to energy metabolism, altered kinetics, regulation of cell death, and dysregulation of calcium-ion homeostasis, and how mitochondrial multi-omics technologies can be utilized to provide us with a better understanding of these processes. In the future, mitochondria-centered therapeutic strategies will be a key idea in the treatment of AD.},
}

*Alzheimer Disease/metabolism/therapy
Humans
*Mitochondria/metabolism
Animals
Genomics/methods
Energy Metabolism
Proteomics/methods

@article {pmid39040086,
year = {2024},
author = {Liu, F and Li, H and Hong, X and Liu, Y and Yu, Z},
title = {Research progress of neuron-specific enolase in cognitive disorder: a mini review.},
journal = {Frontiers in human neuroscience},
volume = {18},
number = {},
pages = {1392519},
pmid = {39040086},
issn = {1662-5161},
abstract = {Numerous studies have demonstrated that neuron-specific enolase (NSE) serves as a distinctive indicator of neuronal injury, with its concentration in blood reflecting the extent and magnitude of nervous system damage, and the expression of serum NSE is correlated with cognitive dysfunction. The assessment of NSE holds significant importance in diagnosing cognitive dysfunction, assessing disease severity, predicting prognosis, and guiding treatment. In this review, the research progress of NSE in cognitive dysfunction was reviewed, and the value of serum NSE level in predicting disease severity and prognosis of patients with cognitive dysfunction was discussed.},
}

@article {pmid39040060,
year = {2024},
author = {Qiao, Y and Mei, Y and Xia, M and Luo, D and Gao, L},
title = {The role of m6A modification in the risk prediction and Notch1 pathway of Alzheimer's disease.},
journal = {iScience},
volume = {27},
number = {7},
pages = {110235},
pmid = {39040060},
issn = {2589-0042},
abstract = {N6-methyladenosine (m6A) methylation and abnormal immune responses are implicated in neurodegenerative diseases, yet their relationship in Alzheimer's disease (AD) remains unclear. We obtained AD datasets from GEO databases and used AD mouse and cell models, observing abnormal expression of m6A genes in the AD group, alongside disruptions in the immune microenvironment. Key m6A genes (YTHDF2, LRPPRC, and FTO) selected by machine learning were associated with the Notch pathway, with FTO and Notch1 displaying the strongest correlation. Specifically, FTO expression decreased and m6A methylation of Notch1 increased in AD mouse and cell models. We further silenced FTO expression in HT22 cells, resulting in upregulation of the Notch1 signaling pathway. Additionally, increased Notch1 expression in dendritic cells heightened inflammatory cytokine secretion in vitro. These results suggest that reduced FTO expression may contribute to the pathogenesis of AD by activating the Notch1 pathway to interfere with the immune response.},
}

@article {pmid39040055,
year = {2024},
author = {Zhang, S and Yuan, J and Sun, Y and Wu, F and Liu, Z and Zhai, F and Zhang, Y and Somekh, J and Peleg, M and Zhu, YC and Huang, Z and , },
title = {Machine learning on longitudinal multi-modal data enables the understanding and prognosis of Alzheimer's disease progression.},
journal = {iScience},
volume = {27},
number = {7},
pages = {110263},
pmid = {39040055},
issn = {2589-0042},
abstract = {Alzheimer's disease (AD) is a complex pathophysiological disease. Allowing for heterogeneity, not only in disease manifestations but also in different progression patterns, is critical for developing effective disease models that can be used in clinical and research settings. We introduce a machine learning model for identifying underlying patterns in Alzheimer's disease (AD) trajectory using longitudinal multi-modal data from the ADNI cohort and the AIBL cohort. Ten biologically and clinically meaningful disease-related states were identified from data, which constitute three non-overlapping stages (i.e., neocortical atrophy [NCA], medial temporal atrophy [MTA], and whole brain atrophy [WBA]) and two distinct disease progression patterns (i.e., NCA → WBA and MTA → WBA). The index of disease-related states provided a remarkable performance in predicting the time to conversion to AD dementia (C-Index: 0.923 ± 0.007). Our model shows potential for promoting the understanding of heterogeneous disease progression and early predicting the conversion time to AD dementia.},
}

@article {pmid39039891,
year = {2024},
author = {Peoples, H and Larsen Maersk, J and Kristensen, HK},
title = {Enabling work for people with dementia - Recommendations for interventions: A mixed-methods review.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012241267122},
doi = {10.1177/14713012241267122},
pmid = {39039891},
issn = {1741-2684},
abstract = {Worldwide, 50 million people are living with dementia. As more individuals develop dementia while still working, dementia will increasingly become a workplace issue and a societal concern. Interventions targeted at work retainment, can reduce, and postpone the loss of cognitive functioning following dementia. However, there is a small body of research focused on recommendations for work interventions for people with dementia. The aim of this mixed-methods review was to investigate experiences of work following a dementia diagnosis from the perspective of people with dementia, their relatives, employers, co-workers and HR-professionals, with the objective of formulating recommendations for work interventions for people with dementia. A mixed-method approach guided the review. 16 original studies published between 1989 to 2023 were included, with a collective sample of 684 participants. The review shows that it is possible to live and work well with dementia, if collaborative solutions are continuously negotiated to meet the needs of the person with dementia and the workplace, and with attention to possible contextual enablers and barriers. The review highlights four key elements for successful work interventions for people with dementia: 1) Person-centered Approach, 2) Contextual Relevance, 3) Knowledge-based and 4) Dynamic Approach.},
}

@article {pmid39039684,
year = {2024},
author = {Kolay, A and Singh, N and Gupta, P and Shaikh, AM and Goel, R and Nagpal, D and Chitme, H},
title = {Immunotherapies: A Treasure Trove of Alzheimer's Disease.},
journal = {Current pharmaceutical biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113892010308600240709052539},
pmid = {39039684},
issn = {1873-4316},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease that falls under the umbrella of dementia and is characterized by the presence of enormously neurotoxic amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein inside the brain. AD remains an intractable global health challenge with limited therapeutic options. Early diagnosis, enabled by biomarkers and neuroimaging, is pivotal for optimizing treatment outcomes. Immunotherapeutic strategies, including monoclonal antibodies, active vaccination, and passive immunization, have been developed to target hallmark AD pathology, such as amyloid-beta aggregation. Here we summarized the emerging role of immunotherapies in the early stages of AD, shedding light on recent breakthroughs and clinical progress. Challenges, including treatment response variability and safety concerns, are discussed alongside evolving approaches, such as personalized immunotherapy and combinatorial treatments. This concise review underscores the promise of immunotherapies as a transformative approach to AD intervention, offering hope for a brighter future in the quest to combat this devastating neurodegenerative disease.},
}

@article {pmid39039682,
year = {2024},
author = {Abidar, S and Hritcu, L and Nhiri, M},
title = {An Overview of the Natural Neuroprotective Agents for the Management of Cognitive Impairment Induced by Scopolamine in Zebrafish (Danio rerio).},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273309256240702053609},
pmid = {39039682},
issn = {1996-3181},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder mainly characterized by dementia and cognitive decline. AD is essentially associated with the presence of aggregates of the amyloid-β peptide and the hyperphosphorylated microtubule-associated protein tau. The available AD therapies can only alleviate the symptoms; therefore, the development of natural treatments that exhibit neuroprotective effects and correct the behavioral impairment is a critical requirement. The present review aims to collect the natural substances that have been evaluated for their neuroprotective profile against AD-like behaviors induced in zebrafish (Danio rerio) by scopolamine. We focused on articles retrieved from the PubMed database via preset searching strings from 2010 to 2023. Our review assembled 21 studies that elucidated the activities of 28 various natural substances, including bioactive compounds, extracts, fractions, commercial compounds, and essential oils. The listed compounds enhanced cognition and showed several mechanisms of action, namely antioxidant potential, acetylcholinesterase's inhibition, and reduction of lipid peroxidation. Additional studies should be achieved to demonstrate their preventive and therapeutic activities in cellular and rodent models. Further clinical trials would be extremely solicited to support more insight into the neuroprotective effects of the most promising drugs in an AD context.},
}

@article {pmid39039681,
year = {2024},
author = {Aghahosseini, F and Salehi, Y and Farzanefar, S and Bakhshi Kashi, M and Eppard, E and Ahmadzadehfar, H and Mirzaei, S and Vahidfar, N and Aghanejad, A},
title = {Recent Advances in the Diagnosis of Alzheimer's Disease: A Brief Overview of Tau PET Tracers in Nuclear Medicine.},
journal = {Current radiopharmaceuticals},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118744710314668240718070109},
pmid = {39039681},
issn = {1874-4729},
abstract = {Dementia (the most common cause of Alzheimer's disease) is defined as a chronic or progressive syndrome with disturbance of multiple cortical functions, the most important of them including memory, learning capacity, comprehension, orientation, calculation, language, and judgement. These cognitive impairments affect the quality of life, behavior, and social relations. Techniques of nuclear medicine provide feasible ways to record the intracellular alterations of disease and deficiencies. In these non-invasive manners, the hippocampal-neocortical disconnection may partly explain the hypo-metabolism incident found in Alzheimer's disease. Based on this fact, the study of all these mechanisms of action is conceivable and achievable by radiopharmaceuticals. This review is aimed at the presentation of radiopharmaceuticals that are developed for the detection of Alzheimer's disease in preclinical and clinical trials.},
}

@article {pmid39039673,
year = {2024},
author = {Rathee, S and Sen, D and Pandey, V and Jain, SK},
title = {Advances in Understanding and Managing Alzheimer's Disease: From Pathophysiology to Innovative Therapeutic Strategies.},
journal = {Current drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113894501320096240627071400},
pmid = {39039673},
issn = {1873-5592},
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the presence of amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles, leading to cognitive and physical decline. Representing the majority of dementia cases, AD poses a significant burden on healthcare systems globally, with onset typically occurring after the age of 65. While most cases are sporadic, about 10% exhibit autosomal forms associated with specific gene mutations. Neurofibrillary tangles and Aβ plaques formed by misfolded tau proteins and Aβ peptides contribute to neuronal damage and cognitive impairment. Currently, approved drugs, such as acetylcholinesterase inhibitors and N-methyl D-aspartate receptor agonists, offer only partial symptomatic relief without altering disease progression. A promising development is using lecanemab, a humanized IgG1 monoclonal antibody, as an immune therapeutic approach. Lecanemab demonstrates selectivity for polymorphic Aβ variants and binds to large soluble Aβ aggregates, providing a potential avenue for targeted treatment. This shift in understanding the role of the adaptive immune response in AD pathogenesis opens new possibilities for therapeutic interventions aiming to address the disease's intricate mechanisms. This review aims to summarize recent advancements in understanding Alzheimer's disease pathology and innovative therapeutic approaches, providing valuable insights for both researchers and clinicians.},
}

@article {pmid39039355,
year = {2024},
author = {Leitner, D and Kavanagh, T and Kanshin, E and Balcomb, K and Pires, G and Thierry, M and Suazo, JI and Schneider, J and Ueberheide, B and Drummond, E and Wisniewski, T},
title = {Differences in the cerebral amyloid angiopathy proteome in Alzheimer's disease and mild cognitive impairment.},
journal = {Acta neuropathologica},
volume = {148},
number = {1},
pages = {9},
pmid = {39039355},
issn = {1432-0533},
support = {P01AG060882/AG/NIA NIH HHS/United States ; P30AG066512/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Cerebral Amyloid Angiopathy/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; *Cognitive Dysfunction/pathology/metabolism ; Male ; Female ; *Proteome/metabolism ; Aged ; Aged, 80 and over ; Proteomics/methods ; },
abstract = {Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta (Aβ) deposition in cerebrovasculature. It is prevalent with aging and Alzheimer's disease (AD), associated with intracerebral hemorrhage, and contributes to cognitive deficits. To better understand molecular mechanisms, CAA(+) and CAA(-) vessels were microdissected from paraffin-embedded autopsy temporal cortex of age-matched Control (n = 10), mild cognitive impairment (MCI; n = 4), and sporadic AD (n = 6) cases, followed by label-free quantitative mass spectrometry. 257 proteins were differentially abundant in CAA(+) vessels compared to neighboring CAA(-) vessels in MCI, and 289 in AD (p < 0.05, fold-change > 1.5). 84 proteins changed in the same direction in both groups, and many changed in the same direction among proteins significant in at least one group (p < 0.0001, R[2] = 0.62). In CAA(+) vessels, proteins significantly increased in both AD and MCI were particularly associated with collagen-containing extracellular matrix, while proteins associated with ribonucleoprotein complex were significantly decreased in both AD and MCI. In neighboring CAA(-) vessels, 61 proteins were differentially abundant in MCI, and 112 in AD when compared to Control cases. Increased proteins in CAA(-) vessels were associated with extracellular matrix, external encapsulating structure, and collagen-containing extracellular matrix in MCI; collagen trimer in AD. Twenty two proteins were increased in CAA(-) vessels of both AD and MCI. Comparison of the CAA proteome with published amyloid-plaque proteomic datasets identified many proteins similarly enriched in CAA and plaques, as well as a protein subset hypothesized as preferentially enriched in CAA when compared to plaques. SEMA3G emerged as a CAA specific marker, validated immunohistochemically and with correlation to pathology levels (p < 0.0001; R[2] = 0.90). Overall, the CAA(-) vessel proteomes indicated changes in vessel integrity in AD and MCI in the absence of Aβ, and the CAA(+) vessel proteome was similar in MCI and AD, which was associated with vascular matrix reorganization, protein translation deficits, and blood brain barrier breakdown.},
}

Humans
*Cerebral Amyloid Angiopathy/pathology/metabolism
*Alzheimer Disease/pathology/metabolism
*Cognitive Dysfunction/pathology/metabolism
Male
Female
*Proteome/metabolism
Aged
Aged, 80 and over
Proteomics/methods

@article {pmid39039352,
year = {2024},
author = {Matsumoto, H and Takaoka, M and Yamamoto-Mitani, N and Igarashi, A},
title = {Development of Four-Item Attitudes toward People Living with Dementia Scale for population surveys.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/psyg.13168},
pmid = {39039352},
issn = {1479-8301},
support = {19H03956//Japan Society for the Promotion of Science/ ; 20J11172//Japan Society for the Promotion of Science/ ; 22K19683//Japan Society for the Promotion of Science/ ; 22K21078//Japan Society for the Promotion of Science/ ; //Eustyle Laboratory, Inc/ ; },
abstract = {BACKGROUND: This study developed a short version of a scale measuring attitudes toward people living with dementia, the Four-Item Attitudes toward People Living with Dementia Scale (APDS4), that could be included in a large population survey.

METHODS: We used three datasets from Japan: a web panel survey, a community-based mail survey, and data from a randomised controlled trial on dementia education. The original scale used was the Attitudes toward People Living with Dementia Scale developed by Kim and Kuroda. Test-retest reliability and item response theory analyses were used to reduce the number of items. The reliability, internal consistency, validity, and responsiveness of the short version were evaluated.

RESULTS: Six items with low test-retest reliability and four items with low discrimination parameters were removed from the 14-item scale. The APDS4, consisting of four items, had test-retest reliability and internal consistency comparable to those of the original scale. Confirmatory factor analysis indicated that the APDS4 fit a unidimensional model. The validity of the APDS4 was confirmed by significant associations between the APDS4 scores and the original scale scores, knowledge of dementia, helping behaviour intentions toward people living with dementia, helping behaviour experience, attending the Dementia Supporter Training Course, and engagement in healthcare jobs. In a randomised controlled trial dataset, the APDS4 was more responsive to educational interventions than the original scale.

CONCLUSION: The shortened APDS4 was established as a reliable, validated, and responsive scale. This scale can be used efficiently in population surveys to evaluate dementia-friendly initiatives at the community level.},
}

@article {pmid39039147,
year = {2024},
author = {Sakurai, K and Tokumaru, AM and Yoshida, M and Saito, Y and Wakabayashi, K and Komori, T and Hasegawa, M and Ikeuchi, T and Hayashi, Y and Shimohata, T and Murayama, S and Iwasaki, Y and Uchihara, T and Sakai, M and Yabe, I and Tanikawa, S and Takigawa, H and Adachi, T and Hanajima, R and Fujimura, H and Hayashi, K and Sugaya, K and Hasegawa, K and Sano, T and Takao, M and Yokota, O and Miki, T and Kobayashi, M and Arai, N and Ohkubo, T and Yokota, T and Mori, K and Ito, M and Ishida, C and Idezuka, J and Toyoshima, Y and Kanazawa, M and Aoki, M and Hasegawa, T and Watanabe, H and Hashizume, A and Niwa, H and Yasui, K and Ito, K and Washimi, Y and Kubota, A and Toda, T and Nakashima, K and Aiba, I and , },
title = {Conventional magnetic resonance imaging key features for distinguishing pathologically confirmed corticobasal degeneration from its mimics: a retrospective analysis of the J-VAC study.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {39039147},
issn = {1432-1920},
support = {20FC1049//Ministry of Health, Labour and Welfare/ ; 23FC1008//Ministry of Health, Labour and Welfare/ ; JP21wm0425019//Japan Agency for Medical Research and Development/ ; JP19dm0107105//Japan Agency for Medical Research and Development/ ; JP20dm0107105//Japan Agency for Medical Research and Development/ ; JP22ek0109545//Japan Agency for Medical Research and Development/ ; },
abstract = {PURPOSE: Due to the indistinguishable clinical features of corticobasal syndrome (CBS), the antemortem differentiation between corticobasal degeneration (CBD) and its mimics remains challenging. However, the utility of conventional magnetic resonance imaging (MRI) for the diagnosis of CBD has not been sufficiently evaluated. This study aimed to investigate the diagnostic performance of conventional MRI findings in differentiating pathologically confirmed CBD from its mimics.

METHODS: Semiquantitative visual rating scales were employed to assess the degree and distribution of atrophy and asymmetry on conventional T1-weighted and T2-weighted images. Additionally, subcortical white matter hyperintensity (SWMH) on fluid-attenuated inversion recovery images were visually evaluated.

RESULTS: In addition to 19 patients with CBD, 16 with CBD mimics (progressive supranuclear palsy (PSP): 9, Alzheimer's disease (AD): 4, dementia with Lewy bodies (DLB): 1, frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa(FTLD-TDP): 1, and globular glial tauopathy (GGT): 1) were investigated. Compared with the CBD group, the PSP-CBS subgroup showed severe midbrain atrophy without SWMH. The non-PSP-CBS subgroup, comprising patients with AD, DLB, FTLD-TDP, and GGT, showed severe temporal atrophy with widespread asymmetry, especially in the temporal lobes. In addition to over half of the patients with CBD, two with FTLD-TDP and GGT showed SWMH, respectively.

CONCLUSION: This study elucidates the distinct structural changes between the CBD and its mimics based on visual rating scales. The evaluation of atrophic distribution and SWMH may serve as imaging biomarkers of conventional MRI for detecting background pathologies.},
}

@article {pmid39039061,
year = {2024},
author = {Du, Y and Zhang, S and Qiu, Q and Fang, Y and Zhao, L and Yue, L and Wang, J and Yan, F and Li, X},
title = {The mediating effect of the amygdala-frontal circuit on the association between depressive symptoms and cognitive function in Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {14},
number = {1},
pages = {301},
pmid = {39039061},
issn = {2158-3188},
mesh = {Humans ; *Amygdala/physiopathology/diagnostic imaging ; *Alzheimer Disease/physiopathology/diagnostic imaging/psychology ; Male ; Female ; Aged ; *Depression/physiopathology/diagnostic imaging ; *Cognition ; Middle Aged ; Diffusion Tensor Imaging ; Cognitive Dysfunction/physiopathology/diagnostic imaging/etiology ; Frontal Lobe/physiopathology/diagnostic imaging ; Neural Pathways/physiopathology ; Case-Control Studies ; Magnetic Resonance Imaging ; Prefrontal Cortex/diagnostic imaging/physiopathology ; },
abstract = {Depressive symptoms occur commonly in Alzheimer's disease (AD). Although abnormalities in the amygdala-frontal circuit have been linked to emotional dysregulation and cognitive impairment, the neurological basis underlying these associations in AD patients with depressive symptoms (ADD) is unclear. We aimed to investigate the relationship between the amygdala-frontal circuit and depressive symptoms and cognitive function in ADD. We recruited 60 ADD, 60 AD patients without depressive symptoms (ADND), and 60 healthy controls (HC). Functional connectivity (FC) maps of the bilateral amygdala were compared. Fractional anisotropy (FA) of the amygdala-frontal circuit connected by the uncinate fasciculus (UF) was calculated using automated fiber quantification (AFQ). In addition, mediation analysis was performed to explore the effects of the amygdala-frontal circuit on the relationship between depressive symptoms and cognitive function. We found decreased bilateral amygdala FC with the inferior frontal gyrus (IFG) in the ADD group compared to the ADND and HC groups. Moreover, FA in the left frontal UF (nodes 64-97) was significantly lower in the ADD group than ADND group. Notably, amygdala-based FC with IFG and the left frontal UF FA mediated the relationship between depressive symptoms and cognitive function in ADD, with mediating effects ranging between 15 and 18%. Our study is the first to demonstrate the mediating effect of functional and microstructural abnormalities in the amygdala-frontal circuit in ADD. The findings suggest that the amygdala-frontal circuit may underlie emotional dysregulation in ADD, providing potential targets for treatment strategies.},
}

Humans
*Amygdala/physiopathology/diagnostic imaging
*Alzheimer Disease/physiopathology/diagnostic imaging/psychology
Male
Female
Aged
*Depression/physiopathology/diagnostic imaging
*Cognition
Middle Aged
Diffusion Tensor Imaging
Cognitive Dysfunction/physiopathology/diagnostic imaging/etiology
Frontal Lobe/physiopathology/diagnostic imaging
Neural Pathways/physiopathology
Case-Control Studies
Magnetic Resonance Imaging
Prefrontal Cortex/diagnostic imaging/physiopathology

@article {pmid39038859,
year = {2024},
author = {Baker, ZG and O'Donnell, MG and Garcia-Arias, S and Huang, Y and Segundo, J and Millenbah, AN and Neubert, OM and Huerta, I},
title = {Protocol for a telephonic mixed methods study to understand needs and find solutions for bereaved dementia caregivers.},
journal = {BMJ open},
volume = {14},
number = {7},
pages = {e086559},
doi = {10.1136/bmjopen-2024-086559},
pmid = {39038859},
issn = {2044-6055},
mesh = {Humans ; *Caregivers/psychology ; *Bereavement ; *Dementia ; *Research Design ; Surveys and Questionnaires ; Qualitative Research ; Needs Assessment ; Telephone ; Alzheimer Disease/psychology/nursing ; Female ; Male ; },
abstract = {INTRODUCTION: Most caregivers of people living with dementia will experience bereavement within 10 years, but study of and support for their needs rarely persists following the death of their care recipients. A single model that leverages theoretical insights as well as observation from lived experience might help identify who will have greater difficulty following dementia-related bereavement and suggest core mechanisms to target to relieve clinical and subclinical consequences. The millions of existing bereaved dementia caregivers likely have considerable insight into ways to improve experience. Rather than creating interventions from scratch, researchers might leverage those insights to more rapidly improve the lives of bereaved dementia caregivers.

METHODS AND ANALYSIS: This study uses a transformative mixed methods approach to explore the needs of caregivers for individuals with Alzheimer's disease (AD) and AD-related dementias, incorporating both quantitative surveys (n=400) and qualitative semistructured interviews (n=45) across diverse subgroups. The study described in this protocol aims to quantitatively test a new model based on self-determination theory to help understand when and why bereaved dementia caregivers experience better and worse outcomes following bereavement. The study also aims to qualitatively explore the ways that bereaved dementia caregivers might meet their needs to inform future interventions.

ETHICS AND DISSEMINATION: The study adheres to institutional guidelines, ensuring participant consent and minimising risks through verbal consent procedures and the removal of personal identifiers from survey responses. The study team will share findings widely through academic publications, conferences and targeted outreach to advocacy groups and healthcare professionals, while also providing concise summaries of results to participants and making them accessible through the lab's website.},
}

Humans
*Caregivers/psychology
*Bereavement
*Dementia
*Research Design
Surveys and Questionnaires
Qualitative Research
Needs Assessment
Telephone
Alzheimer Disease/psychology/nursing
Female
Male

@article {pmid39038839,
year = {2024},
author = {Webster, NJ and Zahodne, LB and Ajrouch, KJ and Antonucci, TC},
title = {Introduction to the Costs of Alzheimer's Disease and Related Dementias.},
journal = {Journal of aging and health},
volume = {},
number = {},
pages = {8982643241265789},
doi = {10.1177/08982643241265789},
pmid = {39038839},
issn = {1552-6887},
abstract = {This special issue is the result of the Michigan Center for Contextual Factors in Alzheimer's Disease (MCCFAD) third Summer Data Immersion (SDI) program held on May 23-26, 2022. Thirty-seven researchers from 17 universities participated in the program, which emphasized racial/ethnic and other contextual factors in the study of Alzheimer's disease and related dementias (ADRD) costs using a team science approach. During the program, data from the Health and Retirement Study were used to investigate multiple topics related to both financial and non-financial costs of ADRD including: (1) life course socioeconomic factors, (2) costs of preclinical ADRD, (3) COVID-19, (4) family members' employment outcomes, (5) geographic contexts, (6) monetary value of unpaid ADRD care, and (7) spousal relations for couples living with ADRD.},
}

@article {pmid39038637,
year = {2024},
author = {Ansari, MM and Sahu, SK and Singh, TG and Singh, S and Kaur, P},
title = {Evolving Significance of Kinase Inhibitors in the Management of Alzheimer's Disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {176816},
doi = {10.1016/j.ejphar.2024.176816},
pmid = {39038637},
issn = {1879-0712},
abstract = {Alzheimer's disease is a neurodegenerative problem with progressive loss of memory and other cognitive function disorders resulting in the imbalance of neurotransmitter activity and signaling progression, which poses the need of the potential therapeutic target to improve the intracellular signaling cascade brought by kinases. Protein kinase plays a significant and multifaceted role in the treatment of Alzheimer's disease, by targeting pathological mechanisms like tau hyperphosphorylation, neuroinflammation, amyloid-beta production and synaptic dysfunction. In this review, we thoroughly explore the essential protein kinases involved in Alzheimer's disease, detailing their physiological roles, regulatory impacts, and the newest inhibitors and compounds that are progressing into clinical trials. All the findings of studies exhibited the promising role of kinase inhibitors in the management of Alzheimer's disease. However, it still poses the need of addressing current challenges and opportunities involved with this disorder for the future perspective of kinase inhibitors in the management of Alzheimer's disease. Further study includes the development of biomarkers, combination therapy, and next-generation kinase inhibitors with increased potency and selectivity for its future prospects.},
}

@article {pmid39038634,
year = {2024},
author = {Parent, JH and Cassady, K and Jagust, WJ and Berry, AS},
title = {Pathological and neurochemical correlates of locus coeruleus functional network activity.},
journal = {Biological psychology},
volume = {},
number = {},
pages = {108847},
doi = {10.1016/j.biopsycho.2024.108847},
pmid = {39038634},
issn = {1873-6246},
abstract = {The locus coeruleus (LC) produces the neuromodulators norepinephrine and dopamine, and projects widely to subcortical and cortical brain regions. The LC has been a focus of neuroimaging biomarker development for the early detection of Alzheimer's disease (AD) since it was identified as one of the earliest brain regions to develop tau pathology. Our recent research established the use of positron emission tomography (PET) to measure LC catecholamine synthesis capacity in cognitively unimpaired older adults. We extend this work by investigating the possible influence of pathology and LC neurochemical function on LC network activity using functional magnetic resonance imaging (fMRI). In separate sessions, participants underwent PET imaging to measure LC catecholamine synthesis capacity ([18F]Fluoro-m-tyrosine), tau pathology ([18F]Flortaucipir), and amyloid-β pathology ([11C]Pittsburgh compound B), and fMRI imaging to measure LC functional network activity at rest. Consistent with a growing body of research in aging and preclinical AD, we find that higher functional network activity is associated with higher tau burden in individuals at risk of developing AD (amyloid-β positive). Critically, relationships between higher LC network activity and higher pathology (amyloid-β and tau) were moderated by LC catecholamine synthesis capacity. High levels of LC catecholamine synthesis capacity reduced relationships between higher network activity and pathology. Broadly, these findings support the view that individual differences in functional network activity are shaped by interactions between pathology and neuromodulator function, and point to catecholamine systems as potential therapeutic targets.},
}

@article {pmid39038422,
year = {2024},
author = {Haque, A and Alenezi, KM and Abdul Rasheed, MSM},
title = {Identification of imidazole-based small molecules to combat cognitive disability caused by Alzheimer's disease: A molecular docking and MD simulations based approach.},
journal = {Computational biology and chemistry},
volume = {112},
number = {},
pages = {108152},
doi = {10.1016/j.compbiolchem.2024.108152},
pmid = {39038422},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is the primary cause of dementia. It is characterised by the gradual loss of brain cells, which results in memory loss and cognitive dysfunction. One of the hallmarks of AD is an abnormally upregulated glutaminyl-peptide cyclotransferase (QPCT or QC) enzyme. Not only AD, but QC has also been implicated with pathological conditions like Huntington's disease (HD), melanomas, carcinomas, atherosclerosis, and septic arthritis. Therefore, the inhibition of QC emerged as a potential strategy for preventing multiple pathological conditions. Considering this, we screened a library of 153,536 imidazole-based compounds against a doubly mutant (Y115E-Y117E) QC target. Molecular docking based virtual screening and absorption, distribution, metabolism, excretion/toxicity (ADME/T) predictions identified five compounds, namely 118981836, 136459842, 139388116, 139388226, and 139958725. Furthermore, molecular dynamics (MD) simulations of 500 ns were conducted to investigate the behaviour of the identified compounds with the target receptor. The results were compared to the co-ligand by analysing RMSD, RMSF, and SASA parameters. To our knowledge, this is the first computational study that employed a protein with double mutation to identify new imidazole-based QC-inhibitors.},
}

@article {pmid39038355,
year = {2024},
author = {Dong, C and Xue, F and Ji, X and Zhang, D},
title = {Analysis and Research on the Relationship between Oral Microorganisms and Alzheimer's Disease.},
journal = {Alternative therapies in health and medicine},
volume = {},
number = {},
pages = {},
pmid = {39038355},
issn = {1078-6791},
abstract = {BACKGROUND: The common neurodegenerative disease among the elderly is Alzheimer's disease, which in severe cases can affect the quality of life of patients and their families. It has been reported that oral microorganisms are involved in the progression of Alzheimer's disease.

OBJECTIVE: To analyze the relationship between oral microorganisms and Alzheimer's disease.

METHODS: The oral microbial population, a comprehensive analysis of relevant literature was conducted. Immunofluorescence was adopted to assess albumin deposition in the cerebral cortex of mice. Western blot was used to detect expression level of CYP46 in mouse brain.

RESULTS: It can be concluded that the population of oral microorganisms includes bacteria, viruses, fungi, and spirochetes, which can cause various oral diseases. They can enter the human brain through the blood and surrounding nerves, leading to permeability increase of the blood-brain barrier and neuroimmune related inflammation. They will participate in and worsen the pathological process of Alzheimer's disease, leading to damage to neurons and cerebral blood vessels. The intervention methods for oral microbiota population include vaccination and phage therapy. Vaccines provide suitable treatment methods for periodontal disease, and phage therapy is a new method for controlling oral infections. At the same time, postoperative patients with oral diseases can use gel containing ethanol extract of Brazilian green propolis to ensure oral hygiene. In the rat blood-brain barrier model, porphyromonas gingivalis bacteremia enhanced barrier permeability, and immunofluorescence showed an increase in albumin deposition in the rat cerebral cortex. The expression of cytochrome P450 46A1 (CYP46A1) enzyme in the brain of Alzheimer's disease mice aged 24-56 weeks after long-term administration of SLAB51 increased.

CONCLUSION: The elderly population should develop good living habits, maintain a clean mouth, and adjust the oral environment through methods such as oral and Alzheimer's disease promotion, combined with medication treatment.},
}

@article {pmid39038282,
year = {2024},
author = {Myers, JR and Bryk, KN and Madero, EN and McFarlane, J and Campitelli, A and Gills, J and Jones, M and Paulson, S and Gray, M and Glenn, JM},
title = {Initial Perspectives From Rural-Residing Adults on a Digital Cognitive Health Coaching Intervention: Exploratory Qualitative Analysis.},
journal = {JMIR formative research},
volume = {8},
number = {},
pages = {e51400},
doi = {10.2196/51400},
pmid = {39038282},
issn = {2561-326X},
abstract = {BACKGROUND: A growing body of research has examined lifestyle-based interventions for dementia prevention. Specifically, health coaching interventions have been linked to decreased risk of Alzheimer disease (AD) comorbidities, such as diabetes. Despite the association, there is a lack of research examining the efficacy and perception of digital health coaching on reducing AD risk. Understanding the perceived benefits of participating in a digital health coach program is critical to ensure long-term use, including participant adherence and engagement.

OBJECTIVE: The purpose of this study is to examine the initial attitudes toward a digital health coaching intervention aimed at preventing cognitive decline among at-risk, rural participants.

METHODS: This exploratory qualitative study is part of the ongoing Digital Cognitive Multidomain Alzheimer Risk Velocity Study (DC-MARVel; ClinicalTrials.gov NCT04559789), a 2-year randomized control trial examining the effects of a digital health coaching intervention on dementia risk, cognitive decline, and general health outcomes. Participants were recruited from the northwest region of Arkansas via word of mouth, email, local radio, and social media. At the time of the analysis, 103 participants randomly assigned to the health coaching group completed an average of 4 coaching sessions over a 4-month period. The intervention included asynchronous messages 1-2 times per week from their health coach that contained health education articles based on the participant's goals (eg, increase physical activity), unlimited access to their coach for questions and recommendations, and monthly meetings with their coach via videoconference or phone to discuss their goals. Participants were asked 2 open-ended questions, "What were your top 1 or 2 takeaways from your recent Health Coaching session?" and "Is there anything you would change about our Health Coaching sessions?" A thematic analysis was conducted using feedback responses from 80 participants (mean age, SD 7.6 years).

RESULTS: The following four themes emerged from participants' feedback: (1) healthy lifestyle and behavioral changes, (2) a sense of self-awareness through introspection, (3) value in coach support, and (4) a desire for a change in program format (eg, frequency). In total, 93% (n=74) of participants expressed that the intervention needed no changes.

CONCLUSIONS: Initial participation in the digital cognitive health coaching intervention was well received, as evidenced by participants reporting value in goal setting and strategies for healthy lifestyle and behavioral changes as well as self-reflection on their personal lifestyle choices. Feedback about their assigned coach also offers insight into the importance of the coach-participant relationship and may serve as a significant factor in overall participant success. Given the exploratory nature of this study, more robust research is needed to elicit more information from participants about their experiences to fully understand the acceptability of the digital health coaching intervention.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04559789; https://clinicaltrials.gov/show/NCT04559789.

RR2-10.2196/31841.},
}

@article {pmid39038100,
year = {2024},
author = {Miranda-Sohrabji, D and Sohrabji, F},
title = {Stroke Literature Synopses (Preclinical).},
journal = {Stroke},
volume = {55},
number = {8},
pages = {e236-e237},
doi = {10.1161/STROKEAHA.124.048026},
pmid = {39038100},
issn = {1524-4628},
mesh = {Animals ; Humans ; *Stroke/therapy ; },
}

Animals
Humans
*Stroke/therapy

@article {pmid39038048,
year = {2024},
author = {Gallo, CM and Kistler, SA and Natrakul, A and Labadorf, AT and Beffert, U and Ho, A},
title = {APOER2 splicing repertoire in Alzheimer's disease: Insights from long-read RNA sequencing.},
journal = {PLoS genetics},
volume = {20},
number = {7},
pages = {e1011348},
doi = {10.1371/journal.pgen.1011348},
pmid = {39038048},
issn = {1553-7404},
abstract = {Disrupted alternative splicing plays a determinative role in neurological diseases, either as a direct cause or as a driver in disease susceptibility. Transcriptomic profiling of aged human postmortem brain samples has uncovered hundreds of aberrant mRNA splicing events in Alzheimer's disease (AD) brains, associating dysregulated RNA splicing with disease. We previously identified a complex array of alternative splicing combinations across apolipoprotein E receptor 2 (APOER2), a transmembrane receptor that interacts with both the neuroprotective ligand Reelin and the AD-associated risk factor, APOE. Many of the human APOER2 isoforms, predominantly featuring cassette splicing events within functionally important domains, are critical for the receptor's function and ligand interaction. However, a comprehensive repertoire and the functional implications of APOER2 isoforms under both physiological and AD conditions are not fully understood. Here, we present an in-depth analysis of the splicing landscape of human APOER2 isoforms in normal and AD states. Using single-molecule, long-read sequencing, we profiled the entire APOER2 transcript from the parietal cortex and hippocampus of Braak stage IV AD brain tissues along with age-matched controls and investigated several functional properties of APOER2 isoforms. Our findings reveal diverse patterns of cassette exon skipping for APOER2 isoforms, with some showing region-specific expression and others unique to AD-affected brains. Notably, exon 15 of APOER2, which encodes the glycosylation domain, showed less inclusion in AD compared to control in the parietal cortex of females with APOE ɛ3/ɛ3 genotype. Also, some of these APOER2 isoforms demonstrated changes in cell surface expression, APOE-mediated receptor processing, and synaptic number. These variations are likely critical in inducing synaptic alterations and may contribute to the neuronal dysfunction underlying AD pathogenesis.},
}

@article {pmid39037949,
year = {2024},
author = {Laghchioua, FE and da Silva, CFM and Pinto, DCGA and Cavaleiro, JAS and Mendes, RF and Paz, FAA and Faustino, MAF and Rakib, EM and Neves, MGPMS and Pereira, F and Moura, NMM},
title = {Design of Promising Thiazoloindazole-Based Acetylcholinesterase Inhibitors Guided by Molecular Docking and Experimental Insights.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.4c00241},
pmid = {39037949},
issn = {1948-7193},
abstract = {Alzheimer's disease is characterized by a progressive deterioration of cognitive function and memory loss, and it is closely associated with the dysregulation of cholinergic neurotransmission. Since acetylcholinesterase (AChE) is a critical enzyme in the nervous system, responsible for breaking down the neurotransmitter acetylcholine, its inhibition holds a significant interest in the treatment of various neurological disorders. Therefore, it is crucial to develop efficient AChE inhibitors capable of increasing acetylcholine levels, ultimately leading to improved cholinergic neurotransmission. The results reported here represent a step forward in the development of novel thiazoloindazole-based compounds that have the potential to serve as effective AChE inhibitors. Molecular docking studies revealed that certain of the evaluated nitroindazole-based compounds outperformed donepezil, a well-known AChE inhibitor used in Alzheimer's disease treatment. Sustained by these findings, two series of compounds were synthesized. One series included a triazole moiety (Tl45a-c), while the other incorporated a carbazole moiety (Tl58a-c). These compounds were isolated in yields ranging from 66 to 87% through nucleophilic substitution and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions. Among the synthesized compounds, the thiazoloindazole-based 6b core derivatives emerged as selective AChE inhibitors, exhibiting remarkable IC50 values of less than 1.0 μM. Notably, derivative Tl45b displays superior performance as an AChE inhibitor, boasting the lowest IC50 (0.071 ± 0.014 μM). Structure-activity relationship (SAR) analysis indicated that derivatives containing the bis(trifluoromethyl)phenyl-triazolyl group demonstrated the most promising activity against AChE, when compared to more rigid substituents such as carbazolyl moiety. The combination of molecular docking and experimental synthesis provides a suitable and promising strategy for the development of new efficient thiazoloindazole-based AChE inhibitors.},
}

@article {pmid39037825,
year = {2024},
author = {Hadad, R and Mandelli, ML and Rankin, KP and Toohey, C and Sturm, VE and Javandel, S and Milicic, A and Knudtson, M and Allen, IE and Hoffmann, N and Friedberg, A and Possin, K and Valcour, V and Miller, BL},
title = {Itching Frequency and Neuroanatomic Correlates in Frontotemporal Lobar Degeneration.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2024.2213},
pmid = {39037825},
issn = {2168-6157},
abstract = {IMPORTANCE: Itching is common in geriatric populations and is frequently linked to dermatological or systemic conditions. Itching engages specific brain regions that are implicated in the pathogenesis of frontotemporal lobar degeneration spectrum disorders (FTLD-SD). Thus, itching of undetermined origin (IUO) may indicate the presence of a neurodegenerative process.

OBJECTIVE: To compare the frequency of itching in FTLD-SD and Alzheimer disease (AD) and to determine the neuroanatomical underpinnings of IUO.

This case-control study evaluated data and brain magnetic resonance images (MRIs) for participants with FTLD-SD or AD. Participants of a research study on FTLD-SD at the University of California, San Francisco, Memory and Aging Center were evaluated from May 1, 2002, to December 31, 2021. The exposure group underwent structural brain MRI within 6 months of initial diagnosis. Research visit summaries were reviewed to validate qualitative details and accurately identify itching with undetermined origin (IUO).

EXPOSURES: Symptoms suggestive of FTLD-SD or AD.

MAIN OUTCOMES AND MEASURES: Frequency of itching in FTLD-SD and AD and neuroanatomic correlates.

RESULTS: A total of 2091 research visit summaries were reviewed for 1112 patients exhibiting symptoms indicative of FTLD-SD or AD. From 795 records where itching or a related phrase was endorsed, 137 had IUO. A total of 454 participants were included in the study: 137 in the itching group (mean [SD] age, 62.7 [9.9] years; 74 [54%] females and 63 males [46%]) and 317 in the nonitching group (mean [SD] age, 60.7 [10.8] years; 154 [49%] females and 163 males [51%]). Groups were similar in age, sex, and disease severity. More frequent itching was found in FTLD-SD (95/248 patients [38%], of which 44 [46%] had behavioral variant frontotemporal dementia [bvFTD]) compared with the AD group (14/77 patients [18%]; P = .001). The odds of itching were 2.4 (95% CI, 1.48-3.97) times higher for FTLD-SD compared with all other cases of dementia. Compared with healthy controls, the group with IUO exhibited greater gray matter atrophy bilaterally in the amygdala, insula, precentral gyrus, and cingulum, as well as in the right frontal superior gyrus and thalamus. Among patients with bvFTD and itching vs bvFTD without itching, itching was associated with right-lateralized gray matter atrophy affecting the insula, thalamus, superior frontal gyrus, and cingulum.

CONCLUSIONS AND RELEVANCE: Among individuals with IUO, FTLD-SD was disproportionately represented compared with AD. In FTLD-SD, dysfunction in the right anterior insula and its connected regions, including the right precentral gyrus, cingulum, and bilateral amygdala, contribute to dysregulation of the itching-scratching networks, resulting in uncontrollable itching or skin picking. Awareness among physicians about the relationship between neurodegeneration and itching may help in the management of itch in older individuals. Further studies are needed to determine the best treatments for these symptoms in patients with neurodegenerative disorders.},
}

@article {pmid39037747,
year = {2024},
author = {Mattke, S and Ozawa, T and Hanson, M},
title = {Implications of treatment duration and frequency for value and cost-effective price of Alzheimer treatments.},
journal = {Journal of managed care & specialty pharmacy},
volume = {},
number = {},
pages = {1-8},
doi = {10.18553/jmcp.2024.24116},
pmid = {39037747},
issn = {2376-1032},
abstract = {BACKGROUND: Disease-modifying Alzheimer treatments are becoming available. The value of the treatments will be attenuated by their complexity of delivery and monitoring, creating additional medical cost and caregiver burden.

OBJECTIVE: To estimate net treatment value using different assumptions for treatment duration and intensity.

METHODS: We estimated the lifetime value of hypothetical treatments that reduce disease progression by 30% from a payer perspective, which considers cost offsets, i.e., reduced medical and formal social care costs, and quality-adjusted life-year gains, and a societal perspective, which adds reduction in caregiver burden. Estimates for gross value of the treatment were based on a prior publication, medical cost on Medicare payment rates, and caregiver time use on a survey of 21 clinics. We analyzed 5 hypothetical treatment scenarios: treatment until progression to moderate dementia with (1) biweekly and (2) 4-weekly infusions, and time-limited infusions every 4 weeks for (3) 72, (4) 52, and (5) 24 weeks.

RESULTS: Treatment until progression to moderate dementia would take 5.7 years and generate gross value of $20,734 in direct cost offsets, $83,761 from a payer and $87,749 from a societal perspective, respectively. Added medical cost and caregiver burden for the 5 scenarios would be $44,179, $24,875, $21,632, $20,416, and $14,350, respectively. The maximum value-based price per year would be $7,687, $11,088, $47,708, $67,273, and $158,954.

CONCLUSIONS: Assuming identical efficacy and safety, the net value generation of time-limited treatment is projected to be larger than that of chronic treatment. Such determination of net lifetime value can be useful to determine value-based prices for different treatment types.},
}

@article {pmid39037560,
year = {2024},
author = {Li, C and Zhao, X and Xu, H and Liu, X and He, Y and Gu, J},
title = {NMN Synbiotics: A Multifaceted Therapeutic Approach for Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {},
number = {},
pages = {},
pmid = {39037560},
issn = {1573-6903},
support = {202019191//Clinical Medical Science and Technology Innovation Program of Jinan/ ; QYPY2020NSFC0601//Cultivation Fund for the First Affiliated Hospital of Shandong First Medical University/ ; ZR2021LSW022//Nature Science Joint Foundation of Shandong Province/ ; 2021TSGC1279//Technological SMEs' innovation ability improvement project/ ; },
abstract = {With the aging global population, Alzheimer's disease (AD) has become a significant social and economic burden, necessitating the development of novel therapeutic strategies. This study investigates the therapeutic potential of nicotinamide mononucleotide (NMN) synbiotics, a combination of NMN, Lactiplantibacillus plantarum CGMCC 1.16089, and lactulose, in mitigating AD pathology. APP/PS1 mice were supplemented with NMN synbiotics and compared against control groups. The effects on amyloid-β (Aβ) deposition, intestinal histopathology, tight junction proteins, inflammatory cytokines, and reactive oxygen species (ROS) levels were assessed. NMN synbiotics intervention significantly reduced Aβ deposition in the cerebral cortex and hippocampus by 67% and 60%, respectively. It also ameliorated histopathological changes in the colon, reducing crypt depth and restoring goblet cell numbers. The expression of tight junction proteins Claudin-1 and ZO-1 was significantly upregulated, enhancing intestinal barrier integrity. Furthermore, NMN synbiotics decreased the expression of proinflammatory cytokines IL-1β, IL-6, and TNF-α, and reduced ROS levels, indicative of attenuated oxidative stress. The reduction in Aβ deposition, enhancement of intestinal barrier function, decrease in neuroinflammation, and alleviation of oxidative stress suggest that NMN synbiotics present a promising therapeutic intervention for AD by modulating multiple pathological pathways. Further research is required to elucidate the precise mechanisms, particularly the role of the NLRP3 inflammasome pathway, which may offer a novel target for AD treatment.},
}

@article {pmid39037476,
year = {2024},
author = {Vasilevskaya, A and Anastassiadis, C and Thapa, S and Taghdiri, F and Khodadadi, M and Multani, N and Rusjan, P and Ozzoude, M and Tarazi, A and Mushtaque, A and Wennberg, R and Houle, S and Green, R and Colella, B and Vasdev, N and Blennow, K and Zetterberg, H and Karikari, T and Sato, C and Moreno, D and Rogaeva, E and Mikulis, D and Davis, KD and Tator, C and Tartaglia, MC},
title = {18F-Flortaucipir (AV1451) imaging identifies grey matter atrophy in retired athletes.},
journal = {Journal of neurology},
volume = {},
number = {},
pages = {},
pmid = {39037476},
issn = {1432-1459},
support = {#2022-01018//Swedish Research Council/ ; #2019-02397//Swedish Research Council/ ; 2017-00915//Swedish Research Council/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; 201809-2016862//Alzheimer's Drug Discovery Foundation/ ; RDAPB-201809-2016615//Alzheimer's Drug Discovery Foundation/ ; #ADSF-21-831376-C//AD Strategic Fund and the Alzheimer's Association/ ; #ADSF-21-831381-C//AD Strategic Fund and the Alzheimer's Association/ ; #ADSF-21-831377-C//AD Strategic Fund and the Alzheimer's Association/ ; FO2022-0270//Hjärnfonden/ ; FO2017-0243//Hjärnfonden/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//UK Dementia Research Institute at UCL/ ; AF-742881//Swedish Alzheimer Foundation/ ; AF-930627//Swedish Alzheimer Foundation/ ; ALFGBG-715986//ALF-agreement/ ; JPND2019-466-236//European Union Joint Program for Neurodegenerative Disorders/ ; 1R01AG068398-01//National Institute of Health (NIH)/ ; A2020812F//BrightFocus Foundation/ ; FO2020-0240//Swedish Brain Foundation/ ; 2020-00124//Agneta Prytz-Folkes & Gösta Folkes Foundation/ ; },
abstract = {BACKGROUND: The long-term consequences of concussions may include pathological neurodegeneration as seen in Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Tau-PET showed promise as a method to detect tau pathology of CTE, but more studies are needed OBJECTIVE: This study aimed (1) to assess the association of imaging evidence of tau pathology with brain volumes in retired athletes and (2) to examine the relationship between tau-PET and neuropsychological functioning.

METHODS: Former contact sport athletes were recruited through the Canadian Football League Alumni Association or the Canadian Concussion Centre clinic. Athletes completed MRI, [[18]F]flortaucipir tau-PET, and a neuropsychological battery. Memory composite was created by averaging the Rey Auditory Verbal Learning Test and Rey Visual Design Learning Test z-scores. Grey matter (GM) volumes were age/intracranial volume corrected using normal control MRIs. Tau-PET % positivity in GM was calculated as the number of positive voxels (≥ 1.3 standardized uptake value ratio (SUVR)/total voxels).

RESULTS: 47 retired contact sport athletes negative for AD (age:51 ± 14; concussions/athlete:15 ± 2) and 54 normal controls (age:50 ± 13) were included. Tau-PET positive voxels had significantly lower GM volumes, compared to tau-PET negative voxels (- 0.37 ± 0.41 vs. - 0.31 ± 0.37, paired p = .006). There was a significant relationship between GM tau-PET % positivity and memory composite score (r =  - .366, p = .02), controlled for age, PET scanner, and PET scan duration. There was no relationship between tau-PET measures and concussion number, or years of sport played.

CONCLUSION: A higher tau-PET signal was associated with reduced GM volumes and lower memory scores. Tau-PET may be useful for identifying those at risk for neurodegeneration.},
}

@article {pmid39037244,
year = {2024},
author = {Yslas, AR and Park, R and Nishimura, N and Lee, E},
title = {Monomeric and oligomeric amyloid-β cause distinct Alzheimer's disease pathophysiological characteristics in astrocytes in human glymphatics-on-chip models.},
journal = {Lab on a chip},
volume = {},
number = {},
pages = {},
doi = {10.1039/d4lc00287c},
pmid = {39037244},
issn = {1473-0189},
abstract = {Alzheimer's disease (AD) is marked by the aggregation of extracellular amyloid-β (Aβ) and astrocyte dysfunction. For Aβ oligomers or aggregates to be formed, there must be Aβ monomers present; however, the roles of monomeric Aβ (mAβ) and oligomeric Aβ (oAβ) in astrocyte pathogenesis are poorly understood. We cultured astrocytes in a brain-mimicking three-dimensional (3D) extracellular matrix and revealed that both mAβ and oAβ caused astrocytic atrophy and hyper-reactivity, but showed distinct Ca[2+] changes in astrocytes. This 3D culture evolved into a microfluidic glymphatics-on-chip model containing astrocytes and endothelial cells with the interstitial fluid (ISF). The glymphatics-on-chip model not only reproduced the astrocytic atrophy, hyper-reactivity, and Ca[2+] changes induced by mAβ and oAβ, but recapitulated that the components of the dystrophin-associated complex (DAC) and aquaporin-4 (AQP4) were properly maintained by the ISF, and dysregulated by mAβ and oAβ. Collectively, mAβ and oAβ cause distinct AD pathophysiological characteristics in the astrocytes.},
}

@article {pmid39037002,
year = {2024},
author = {Simone, M and Pulpito, M and Perna, FM and Capriati, V and Vitale, P},
title = {Switchable Deep Eutectic Solvents for Sustainable Sulfonamide Synthesis.},
journal = {Chemistry (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e202402293},
doi = {10.1002/chem.202402293},
pmid = {39037002},
issn = {1521-3765},
abstract = {A sustainable and scalable protocol for synthesizing variously functionalized sulfonamides, from amines and sulfonyl chlorides, has been developed using environmentally responsible and reusable choline chloride (ChCl)-based deep eutectic solvents (DESs). In ChCl/glycerol (1:2 mol mol-1) and ChCl/urea (1:2 mol mol-1), these reactions yield up to 97% under aerobic conditions at ambient temperature within 2-12 h. The practicality of the method is exemplified by the sustainable synthesis of an FFA4 agonist and a key building block en route to anti-Alzheimer drug BMS-299897. A subtle interplay of electronic effects and the solubility characteristics of the starting materials in the aforementioned DESs seem to be responsible for driving the reaction successfully over the hydrolysis of sulfonyl chlorides. The procedure's eco-friendliness is validated by quantitative metrics like the E-factor and the EcoScale, with products isolated by extraction or filtration after decantation.},
}

@article {pmid39036920,
year = {2024},
author = {Kong, LWY and He, XT and Chen, FM and Li, X},
title = {[Influence of periodontal microbial homeostasis on neurodegenerative diseases and its therapeutic perspectives].},
journal = {Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology},
volume = {59},
number = {8},
pages = {852-857},
doi = {10.3760/cma.j.cn112144-20231027-00225},
pmid = {39036920},
issn = {1002-0098},
support = {82301079, 82371010//National Natural Science Foundation of China/ ; 2022QNRC001//The Young Elite Scientist Sponsorship Program by CAST/ ; },
abstract = {The oral cavity is the second largest reservoir of microorganisms in the human body, containing more than 700 species. Periodontal microorganisms are an important part of oral microorganisms. Plaque biofilm, the initiator of periodontal disease, contains an abundance of oral microorganisms. The special complex anatomy of the periodontium allows for a higher abundance of the periodontal microbiota. There are growing evidences show that the periodontal microbiota is not only closely associated with oral diseases, but also plays an important role in mouth-brain interactions. Dysbiosis of the periodontal microbiota may facilitate the progression of neurodegenerative diseases including Alzheimer disease, Parkinson disease, and multiple sclerosis. Here, this paper reviews the bidirectional role of periodontal microbiota between the oral cavity and the brain, that is, the bridge effect of periodontal microbiota involved in the interaction between the two diseases, enumerates the epidemiological and biological evidences that dysregulation of the periodontal microbiota induces and exacerbates neurodegenerative diseases, and analyzes their possible mechanisms. The positive implications of periodontal microbial homeostasis in the prevention and treatment of neurodegenerative diseases are described with the aim of providing new ideas and insights into the pathogenesis and therapeutic approaches for neurodegenerative diseases.},
}

@article {pmid39036818,
year = {2024},
author = {Basile, S and Parisi, C and Bellia, F and Zimbone, S and Arrabito, G and Gulli, D and Pignataro, B and Giuffrida, ML and Sortino, S and Copani, A},
title = {Red-Light-Photosensitized Tyrosine 10 Nitration of β-Amyloid1-42 Diverts the Protein from Forming Toxic Aggregates.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.4c00284},
pmid = {39036818},
issn = {1948-7193},
abstract = {Several studies have highlighted the presence of nitration damage following neuroinflammation in Alzheimer's disease (AD). Accordingly, post-transcriptional modifications of β-amyloid (Aβ), including peptide nitration, have been explored as a marker of the disease. However, the implications of Aβ nitration in terms of aggregation propensity and neurotoxicity are still debated. Here, we show new data obtained using a photoactivatable peroxynitrite generator (BPT-NO) to overcome the limitations associated with chemical nitration methods. We found that the photoactivation of BPT-NO with the highly biocompatible red light selectively induces the nitration of tyrosine 10 of freshly solubilized full-length Aβ1-42. Photonitrated Aβ1-42 was, therefore, investigated for aggregation states and functions. It resulted that photonitrated Aβ1-42 did not aggregate into small oligomers but rather self-assembled into large amorphous aggregates. When tested on neuronal-like SH-SY5Y cells and microglial C57BL/6 BV2 cells, photonitrated Aβ1-42 showed to be free of neurotoxicity and able to induce phagocytic microglia cells. We propose that light-controlled nitration of the multiple forms in which Aβ occurs (i.e., monomers, oligomers, fibrils) could be a tool to assess in real-time the impact of tyrosine nitration on the amyloidogenic and toxic properties of Aβ1-42.},
}

@article {pmid39036736,
year = {2024},
author = {Kim, B and Kim, YS and Li, W and Kwon, EB and Chung, HS and Go, Y and Choi, JG},
title = {Ginsenoside Rg5, a potent agonist of Nrf2, inhibits HSV-1 infection-induced neuroinflammation by inhibiting oxidative stress and NF-κB activation.},
journal = {Journal of ginseng research},
volume = {48},
number = {4},
pages = {384-394},
pmid = {39036736},
issn = {1226-8453},
abstract = {BACKGROUND: Herpes simplex virus type 1 (HSV-1), known to latently infect the host's trigeminal ganglion, can lead to severe herpes encephalitis or asymptomatic infection, potentially contributing to neurodegenerative diseases like Alzheimer's. The virus generates reactive oxygen species (ROS) that significantly impact viral replication and induce chronic inflammation through NF-κB activation. Nuclear factor E2-related factor 2 (Nrf2), an oxidative stress regulator, can prevent and treat HSV-1 infection by activating the passive defense response in the early stages of infection.

METHODS AND RESULTS: Our study investigated the antiviral effects of ginsenoside Rg5, an Nrf2 activator, on HSV-1 replication and several host cell signaling pathways. We found that HSV-1 infection inhibited Nrf2 activity in host cells, induced ROS/NF-κB signaling, and triggered inflammatory cytokines. However, treatment with ginsenoside Rg5 inhibited ROS/NF-κB signaling and reduced inflammatory cytokines through NRF2 induction. Interestingly, the Nrf2 inhibitor ML385 suppressed the expression of NAD(P)H quinone oxidoreductase 1(NQO1) and enhanced the expression of KEAP1 in HSV-1 infected cells. This led to the reversal of VP16 expression inhibition, a protein factor associated with HSV-1 infection, thereby promoting HSV-1 replication.

CONCLUSION: These findings suggest for the first time that ginsenoside Rg5 may serve as an antiviral against HSV-1 infection and could be a novel therapeutic agent for HSV-1-induced neuroinflammation.},
}

@article {pmid39036641,
year = {2024},
author = {He, J and Wu, J and Liu, J and Wu, H and Hua, H},
title = {Cognitive impairment and the gut-brain axis during 2014-2023: a bibliometric analysis.},
journal = {Frontiers in neurology},
volume = {15},
number = {},
pages = {1407956},
pmid = {39036641},
issn = {1664-2295},
abstract = {BACKGROUND: The burden on society grows as the number of individuals with cognitive impairment rises. Numerous research have discovered a connection between cognitive impairment and the gut-brain axis, which is useful in examining the pathophysiology of cognitive impairment and potential therapeutic approaches. As a result, this article explores developments and trends in the research concerning the gut-brain axis and cognitive impairment through a bibliometric analysis of the contributions made by various countries/regions, institutions, authors, and journals.

METHODS: We looked for articles on gut-brain axis and cognitive impairment from 2014 to 2023 in the Web of Science Core Collection. For the descriptive analysis, figures and tables were taken using GraphPad Prism 6 and WPS Office 2024. For the visual analysis of the countries/regions, institutions, authors, and keywords, VOSviewer was utilized.

RESULTS: We obtained 458 publications from 1 January 2014 to 9 September 2023. The country with the most publications (175, 38.21%) was China. The country with the greatest total number of citations (3,138, 17.22%) was the United States of America. The highest number of articles (15, 3.26%) was issued by Zhejiang University. The most published first author is Karsas M. In this field, Nutrients have published the most articles (24). The most often occurring keywords include "Alzheimer's disease," "cognitive impairment," "gut microbiota," "inflammation," "diet," etc. "Stroke," "tau," "probiotics," "exercise," "fecal microbiota transplantation," etc. emerged later.

CONCLUSION: An increasing amount of research has focused on the connection between cognitive impairment and the gut-brain axis. In this area, the United States of America and China have both made significant contributions. The author team's collaboration has to be improved. Our study contributes to understanding the field's current state and predicting its future trend.},
}

@article {pmid39036627,
year = {2024},
author = {Yokoi, Y and Inagawa, T and Yamada, Y and Matsui, M and Tomizawa, A and Noda, T},
title = {A randomized sham-controlled trial of transcranial and intranasal photobiomodulation in Japanese patients with mild cognitive impairment and mild dementia due to Alzheimer's disease: a protocol.},
journal = {Frontiers in neurology},
volume = {15},
number = {},
pages = {1371284},
pmid = {39036627},
issn = {1664-2295},
abstract = {INTRODUCTION: Photobiomodulation (PBM) is a novel strategy for cognitive enhancement by improving brain metabolism and blood flow. It is potentially beneficial for patients with Alzheimer's disease (AD). We present a study protocol for a randomised controlled trial designed to evaluate the efficacy and safety of PBM.

METHOD AND ANALYSIS: This is a single-centre, parallel-group, randomised, sham-controlled study. We enroll patients with mild cognitive impairment or dementia due to AD and assigned them to receive either active or sham stimulation at home for 12 weeks, with three sessions per week (20 min each). The stimulation involves invisible near-infrared light delivered by five applicators (one in a nostril, one on the frontal scalp, and three on the occipital scalp). The primary outcome will be the mean change in the Alzheimer Disease Assessment Scale-cognition from baseline to Week 12. We will also measure cognitive function, activity of daily living, behavioral and psychological symptoms, and caregiver burden. We will collect data at clinics at baseline and Week 12 and remotely at home. We estimate a sample size of 30 (20 active and 10 sham) based on an expected mean difference of -6.9 and an SD of 4.8. We use linear models for the statistical analysis.

ETHICS AND DISSEMINATION: The National Center of Neurology and Psychiatry Clinical Research Review Board (CRB3200004) approved this study. The results of this study will be published in a scientific peer-reviewed journal. Trial registration details Japan Registry of Clinical Trials jRCTs032230339.},
}

@article {pmid39036341,
year = {2024},
author = {You, M and Chen, N and Yang, Y and Cheng, L and He, H and Cai, Y and Liu, Y and Liu, H and Hong, G},
title = {The gut microbiota-brain axis in neurological disorders.},
journal = {MedComm},
volume = {5},
number = {8},
pages = {e656},
pmid = {39036341},
issn = {2688-2663},
abstract = {Previous studies have shown a bidirectional communication between human gut microbiota and the brain, known as the microbiota-gut-brain axis (MGBA). The MGBA influences the host's nervous system development, emotional regulation, and cognitive function through neurotransmitters, immune modulation, and metabolic pathways. Factors like diet, lifestyle, genetics, and environment shape the gut microbiota composition together. Most research have explored how gut microbiota regulates host physiology and its potential in preventing and treating neurological disorders. However, the individual heterogeneity of gut microbiota, strains playing a dominant role in neurological diseases, and the interactions of these microbial metabolites with the central/peripheral nervous systems still need exploration. This review summarizes the potential role of gut microbiota in driving neurodevelopmental disorders (autism spectrum disorder and attention deficit/hyperactivity disorder), neurodegenerative diseases (Alzheimer's and Parkinson's disease), and mood disorders (anxiety and depression) in recent years and discusses the current clinical and preclinical gut microbe-based interventions, including dietary intervention, probiotics, prebiotics, and fecal microbiota transplantation. It also puts forward the current insufficient research on gut microbiota in neurological disorders and provides a framework for further research on neurological disorders.},
}

@article {pmid39036178,
year = {2024},
author = {Mundada, M and Diggikar, PM and Shokeen, A and Reddy, RH and Oommen, AB and Pancholi, T and Yammanuru, B and Yekkaluru, SV and R, J and Jagirdar, A},
title = {Comprehensive Analysis of Dementia Types and Risk Factors: A Study From a Tertiary Care Center in India.},
journal = {Cureus},
volume = {16},
number = {6},
pages = {e62745},
pmid = {39036178},
issn = {2168-8184},
abstract = {Background and objective Dementia is a prevalent clinical syndrome characterized by memory impairment and cognitive dysfunction. Its global burden is expected to rise significantly, particularly in low- and middle-income countries. Understanding the spectrum of dementia types and associated risk factors is crucial for effective management. This study aims to elucidate the demographic profiles, clinical types, and risk factors of newly diagnosed dementia cases at a tertiary care hospital in India. Methods and materials A cross-sectional, hospital-based observational study was conducted on 81 patients at the Department of Medicine, Dr. D. Y. Patil Medical College, Hospital, and Research Centre, Pimpri, Pune, from February 2022 to January 2024. Ethical approval was obtained, and written consent was obtained from participants. Clinical diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria, supported by cognitive assessment tools and laboratory/radiological investigations. Inclusion criteria encompassed individuals aged 18 years or older, presenting with clinical symptoms suggestive of dementia, having a Mini-Mental State Examination (MMSE) score of less than 24 and Montreal Cognitive Assessment (MoCA) score of less than 25, according to DSM-V criteria for dementia. Exclusion criteria included individuals with a history of head trauma or those below 18 years of age. Results Of the 81 participants, the majority (74.1%) were over 60 years old, with females comprising 59.3% of the sample. Alzheimer's disease was the most prevalent dementia subtype (34.5%), followed by vascular dementia (19.7%) and mixed dementia (13.5%). Other causes included Lewy body dementia (2.46%), Parkinson's dementia (4.9%), frontotemporal dementia (4.9%), and Creutzfeldt-Jakob disease (1.2%). Reversible causes accounted for a significant proportion of cases: alcohol-associated dementia (6.1%), hypothyroid-associated dementia (3.7%), HIV-associated dementia (2.46%), herpes simplex dementia (1.2%), neurosyphilis-associated dementia (1.2%), and normal pressure hydrocephalus (NPH)-associated dementia (2.4%). Analysis of risk factors revealed distinct patterns among different dementia types, emphasizing the role of cardiovascular and metabolic health. Conclusion This study provides insights into the demographic profiles, clinical types, and dementia risk factors in India. Addressing causes and managing cardiovascular/metabolic health is crucial for dementia prevention and management. Comprehensive care strategies and ongoing research efforts are essential for improving dementia outcomes and enhancing the quality of life for affected individuals and their families.},
}

@article {pmid39036141,
year = {2024},
author = {Reddy, P and Devarakonda, PK and Gotlieb, G and Moreno, P},
title = {A Case Report Highlighting the Significance of COVID-19 Unveiling Megaloblastic Anemia and Worsening Dementia in the Elderly.},
journal = {Cureus},
volume = {16},
number = {6},
pages = {e62836},
pmid = {39036141},
issn = {2168-8184},
abstract = {The COVID-19 pandemic has resulted in substantial lifestyle changes with significant implications for nutritional health. Factors such as movement restrictions and disruptions in food supply chains led to the restricted availability of primary sources of essential micronutrients. To highlight this, we present the case of an elderly woman with an underlying subclinical cobalamin deficiency who developed symptomatic megaloblastic anemia, requiring hospital admission under lockdown conditions. This exemplifies how changes in diet during the COVID-19 lockdown have hastened the onset of B12 deficiency symptoms. Adverse outcomes can be avoided by identifying people at high risk of poor nutritional status and implementing policy initiatives that enhance their nutritional condition. This case report showed how important the B12 shortage was during the COVID-19 lockdown, especially for older people. They are more likely to be malnourished during COVID-19 for several reasons.},
}

@article {pmid39035579,
year = {2024},
author = {Sadeghi, G and Dinani, MS and Rabbani, M},
title = {Effects of extracts and manna of Echinops cephalotes on impaired cognitive function induced by scopolamine in mice.},
journal = {Research in pharmaceutical sciences},
volume = {19},
number = {2},
pages = {167-177},
pmid = {39035579},
issn = {1735-5362},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a neurodegenerative disease specified by chronic and irreversible destruction of neurons. This study aimed to evaluate the effects of different extracts (aqueous, hydroalcoholic, hexane, and ethyl acetate) and manna of Echinops cephalotes (EC) on impaired cognitive function induced by scopolamine in mice. EC is shown to have anti-cholinesterase-butyrylcholinesterase activities.

EXPERIMENTAL APPROACH: In this study, aqueous and hydroalcoholic extracts, hexane and ethyl acetate fractions of EC (25, 50, 100 mg/kg, i.p.), and the manna (25, 50, 100 mg/kg, gavage) were administered for 14 days alongside scopolamine (0.7 mg/kg, i.p.). Rivastigmine (reference drug) was administered for 2 weeks i.p. Mice were tested for their memory function using two behavioral models, object recognition test (ORT) and passive avoidance test (PAT).

FINDINGS/RESULTS: Administration of scopolamine significantly impaired memory function in both behavioral models. In the PAT model, all extracts at 50 and 100 mg/kg significantly reversed the effect of memory destruction caused by scopolamine. At a lower dose of 25 mg/kg, however, none of the extracts were able to significantly change the step-through latency time. In the ORT model, however, administration of all extracts at 50 and 100 mg/kg, significantly increased the recognition index. Only the manna and the aqueous extract at 25 mg/kg were able to reverse scopolamine-induced memory impairment.

CONCLUSIONS AND IMPLICATIONS: These results suggest that all forms of EC extracts improve memory impairment induced by scopolamine comparably to rivastigmine. Whether the effects are sustained over a longer period remains to be tested in future work.},
}

@article {pmid39035497,
year = {2024},
author = {Almasi, S and Jafarzadeh Shirazi, MR and Rezvani, MR and Ramezani, M and Salehi, I and Pegah, A and Komaki, A},
title = {The protective effect of biotin supplementation and swimming training on cognitive impairment and mental symptoms in a rat model of Alzheimer's disease: A behavioral, biochemical, and histological study.},
journal = {Heliyon},
volume = {10},
number = {13},
pages = {e32299},
pmid = {39035497},
issn = {2405-8440},
abstract = {Vitamin B (Vit B) plays a regulatory role in cognitive memory and learning. We examined the biochemical and behavioral effects of biotin supplementation (BS) and swimming training (ST) on Alzheimer's disease (AD), the most common type of dementia, in male rats. Sixty rats were randomly assigned to six groups: control, sham (receiving phosphate-buffered saline), AD (receiving a single injection of Aβ into the lateral ventricle), ST (for 28 days and before Aβ injection), and BS (receiving BS through oral gavage for 28 days before Aβ injection). The treatments were continued until the end of the behavioral tests. Learning and memory functions were investigated through the Morris water maze (MWM) and depression and anxiety-like behaviors were tested by elevated plus-maze (EPM) and forced swimming tests. In addition, oxidative stress biomarkers, such as total thiol groups (TTG) and malondialdehyde (MDA) in serum were assessed and histological studies were performed using brain tissues. In the AD group, Aβ increased the distance traveled and escape latency in the MWM, but co-administration of BS and ST attenuated the results of the MWM, EPM, and FST tests. Furthermore, BS decreased the litigious biochemical effects of Aβ by enhancing the levels of TTG, in addition to reducing serum MDA levels. The use of BS as a potent antioxidant improved Aβ-induced memory impairment. It attenuated oxidative stress biomarkers in the brain (number of Aβ plaques) and serum of AD rats. We provide evidence for the use of BS in neurodegenerative disorders, such as AD, to elucidate the possible mechanisms.},
}

@article {pmid39035420,
year = {2024},
author = {Tang, J and Huang, H and Muirhead, RCJ and Zhou, Y and Li, J and DeFelice, J and Kopanitsa, MV and Serneels, L and Davey, K and Tilley, BS and Gentleman, S and Matthews, PM},
title = {Associations of amyloid-β oligomers and plaques with neuropathology in the App [NL-G-F] mouse.},
journal = {Brain communications},
volume = {6},
number = {4},
pages = {fcae218},
pmid = {39035420},
issn = {2632-1297},
abstract = {Amyloid-β pathology and neurofibrillary tangles lead to glial activation and neurodegeneration in Alzheimer's disease. In this study, we investigated the relationships between the levels of amyloid-β oligomers, amyloid-β plaques, glial activation and markers related to neurodegeneration in the App [NL-G-F] triple mutation mouse line and in a knock-in line homozygous for the common human amyloid precursor protein (App [hu] mouse). The relationships between neuropathological features were characterized with immunohistochemistry and imaging mass cytometry. Markers assessing human amyloid-β proteins, microglial and astrocytic activation and neuronal and synaptic densities were used in mice between 2.5 and 12 months of age. We found that amyloid-β oligomers were abundant in the brains of App [hu] mice in the absence of classical amyloid-β plaques. These brains showed morphological changes consistent with astrocyte activation but no evidence of microglial activation or synaptic or neuronal pathology. In contrast, both high levels of amyloid-β oligomers and numerous plaques accumulated in App [NL-G-F] mice in association with substantial astrocytic and microglial activation. The increase in amyloid-β oligomers over time was more strongly correlated with astrocytic than with microglia activation. Spatial analyses suggested that activated microglia were more closely associated with amyloid-β oligomers than with amyloid-β plaques in App [NL-G-F] mice, which also showed age-dependent decreases in neuronal and synaptic density markers. A comparative study of the two models highlighted the dependence of glial and neuronal pathology on the nature and aggregation state of the amyloid-β peptide. Astrocyte activation and neuronal pathology appeared to be more strongly associated with amyloid-β oligomers than with amyloid-β plaques, although amyloid-β plaques were associated with microglia activation.},
}

@article {pmid39035417,
year = {2024},
author = {Estarellas, M and Oxtoby, NP and Schott, JM and Alexander, DC and Young, AL},
title = {Multimodal subtypes identified in Alzheimer's Disease Neuroimaging Initiative participants by missing-data-enabled subtype and stage inference.},
journal = {Brain communications},
volume = {6},
number = {4},
pages = {fcae219},
pmid = {39035417},
issn = {2632-1297},
abstract = {Alzheimer's disease is a highly heterogeneous disease in which different biomarkers are dynamic over different windows of the decades-long pathophysiological processes, and potentially have distinct involvement in different subgroups. Subtype and Stage Inference is an unsupervised learning algorithm that disentangles the phenotypic heterogeneity and temporal progression of disease biomarkers, providing disease insight and quantitative estimates of individual subtype and stage. However, a key limitation of Subtype and Stage Inference is that it requires a complete set of biomarkers for each subject, reducing the number of datapoints available for model fitting and limiting applications of Subtype and Stage Inference to modalities that are widely collected, e.g. volumetric biomarkers derived from structural MRI. In this study, we adapted the Subtype and Stage Inference algorithm to handle missing data, enabling the application of Subtype and Stage Inference to multimodal data (magnetic resonance imaging, positron emission tomography, cerebrospinal fluid and cognitive tests) from 789 participants in the Alzheimer's Disease Neuroimaging Initiative. Missing-data Subtype and Stage Inference identified five subtypes having distinct progression patterns, which we describe by the earliest unique abnormality as 'Typical AD with Early Tau', 'Typical AD with Late Tau', 'Cortical', 'Cognitive' and 'Subcortical'. These new multimodal subtypes were differentially associated with age, years of education, Apolipoprotein E (APOE4) status, white matter hyperintensity burden and the rate of conversion from mild cognitive impairment to Alzheimer's disease, with the 'Cognitive' subtype showing the fastest clinical progression, and the 'Subcortical' subtype the slowest. Overall, we demonstrate that missing-data Subtype and Stage Inference reveals a finer landscape of Alzheimer's disease subtypes, each of which are associated with different risk factors. Missing-data Subtype and Stage Inference has broad utility, enabling the prediction of progression in a much wider set of individuals, rather than being restricted to those with complete data.},
}

@article {pmid39035235,
year = {2024},
author = {Tessaro, I and Hooper, SM and Watt, D and Menestres, D and Farrell, D},
title = {Development of an online tool to support financial and legal planning in dementia.},
journal = {PEC innovation},
volume = {5},
number = {},
pages = {100312},
pmid = {39035235},
issn = {2772-6282},
abstract = {OBJECTIVE: To develop, assess, and refine an online educational tool, Plan for Clarity, to support financial and legal planning in dementia.

METHODS: A Delphi mixed-method study with three rounds of anonymous review by lay and professional stakeholders was designed to reach consensus about the content of the online tool and explore the socio-cultural and behavioral factors that could affect access and use.

RESULTS: Consensus showed that the online tool covered key information, knowledge, and communication skills for financial and legal planning. Study themes: 1) the online tool had to be easy to navigate with relevant, easily understood information; 2) people with early signs of memory difficulties would be able to use the tool; 3) a referral from a trusted source is a primary way to facilitate access and use of the tool; and 4) discussions about financial and legal issues should be held early, ahead of barriers that can block discussion.

CONCLUSION: These data suggest this online tool is relevant and feasible for dementia care and support as well as aging more generally.

INNOVATION: Plan for Clarity is innovative as an evidence and theory-driven online education tool to address financial and legal planning for dementia care, particularly among underserved older adults.},
}

@article {pmid39035234,
year = {2024},
author = {Wang, Q and Zhen, W and Hu, R and Wang, Z and Sun, Y and Sun, W and Huang, C and Xu, J and Zhang, H},
title = {Occlusion dysfunction and Alzheimer's disease: Mendelian randomization study.},
journal = {Frontiers in aging neuroscience},
volume = {16},
number = {},
pages = {1423322},
pmid = {39035234},
issn = {1663-4365},
abstract = {AIM: Occlusion dysfunction (OD) is increasingly linked to Alzheimer's disease (AD). This study aimed to elucidate the causal relationship between OD and AD using Mendelian randomization (MR) analysis.

MATERIALS AND METHODS: Genome-wide association study (GWAS) meta-analysis data obtained from FinnGen, IEU Open GWAS, and UK Biobank (UKBB) was represented as instrumental variables. We validated the causal relationship between periodontal disease (PD), loose teeth (PD & occlusion dysfunction), dentures restoration (occlusion recovery), and AD.

RESULTS: According to the MR analysis, PD and AD have no direct causal relationship (P = 0.395, IVW). However, loose teeth significantly increased the risk of AD progression (P = 0.017, IVW, OR = 187.3567, 95%CI = 2.54E+00-1.38E+04). These findings were further supported by the negative causal relationship between dentures restoration and AD (P = 0.015, IVW, OR = 0.0234, 95%CI = 1.13E-03-0.485).

CONCLUSION: The occlusion dysfunction can ultimately induce Alzheimer's disease. Occlusion function was a potentially protective factor for maintaining neurological health.},
}