bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and sustainability of 40 Hz high‐definition transcranial alternating current stimulation (tACS) in the treatment of sleep disturbances in mild neurocognitive disorders due to Alzheimer’s disease
Authors: Lu Hanna , Li Jing , Ni Xi , Yang Natalie Shu , Wing Yun Kwok , Ma Suk Ling , Lam Linda Chiu Wa , Zhang Li 
Published: January 2025

AbstractBackgroundTo investigate the effects of 40 Hz high‐definition transcranial alternating current stimulation (HD‐tACS) on subjective sleep quality and domain‐specific cognitive functions in mild neurocognitive disorders due to Alzheimer’s disease (NCD‐AD).MethodThis study was a double blind, sham‐controlled randomized clinical trial. Ninety‐nine mild NCD‐AD patients were randomly assigned to receive a 4‐week course treatment of either 40 Hz HD‐tACS, HD transcranial direct current stimulation (HD‐tDCS), or sham transcranial current stimulation (HD‐tCS). Global cognition was assessed by Montreal Cognitive Assessment (MoCA). Subjective sleep quality was assessed by Pittsburgh Sleep Quality Index (PSQI). PSQI total score>5 was defined as sleep disturbances.ResultThe mean score of PSQI was 11.7 in mild NCD‐AD patients. Repeated sessions of 40 Hz HD‐tACS and HD‐tDCS treatments significantly enhanced the subjective sleep quality and cognition. Compared with HD‐tDCS, the individuals who received 40 Hz HD‐tACS had more improvement on sleep quality (score changes of PSQI: 6.01 vs. 3.72, p<0.001) and cognitive function (MoCA: 2.5 vs.1.5, p<0.01) during a 2‐month follow‐up period.ConclusionMild NCD‐AD patients with sleep disturbances who received 40 Hz HD‐tACS had pronounced enhancement in subjective sleep quality and global cognition. To identify novel modality of transcranial brain stimulation is important toward an effective strategy for the comorbidities in preclinical AD.
Does Neurodegeneration Lag Behind Tau Deposition in Alzheimer Dementia?
Authors: Shah Ujashi , Xie Long , McGrew Emily , Wolk David A , Das Sandhitsu R. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is defined by the presence of ß‐amyloid (Aß) plaques and tau‐based neurofibrillary tangles (NFTs). Understanding the temporal relationship of NFTs with atrophy in early AD regions, specifically the medial temporal lobe (MTL), is critical for monitoring disease progression. Accumulation of NFTs has been suggested to precede atrophy because cross‐sectional measures of atrophy are more weakly associated with baseline tracer uptake than prospective longitudinal ones. However, longitudinal measures may be more sensitive to disease‐related atrophy at early AD stages. To address this, we examine cross‐sectional versus longitudinal measures before or after the time of tau PET.MethodsData from patients with mild cognitive impairment (MCI) or dementia due to AD (n = 69, amyloid PET positive (Aß+) symptomatic adults) were analyzed. Tau PET date was the anchor point and MRI atrophy measures from earlier, ≤2 years before, and later, ≤2 years after, scans were derived. Hippocampal volumes and thickness of Brodmann area (BA) 35, the region of earliest tau accumulation, as well as their annualized rates of volume loss were extracted as atrophy measures. MTL tau was measured as tracer uptake in a combined BA35/ERC region. Cross‐sectional and longitudinal analyses included Pearson correlation between MTL tau and atrophy and Pearson and Filon’s z test to compare these correlations.ResultsAs expected, there was a significant correlation between atrophy and tau in the cross‐sectional analysis, which was generally stronger for later time points. Specifically, there was a statistically significant difference (p <0.05) for right hippocampal volume and BA35 thickness. In longitudinal data, while the correlation between annualized atrophy rate and tau was generally greater at both time points compared to the cross‐sectional data, these longitudinal correlations did not differ between the two time points.ConclusionsHere we show longitudinal atrophy rates before or after tau scans are similarly correlated. Later cross‐sectional measures have stronger correlations than earlier, likely due to more time to accrue atrophy relative to other sources of variation. These results question prior arguments of a lag between deposition and atrophy, which may be based on differences of sensitivity of cross‐sectional and longitudinal measures.
Longitudinal effects of gantenerumab treatment on amyloid‐PET‐derived perfusion estimates in an early AD population
Authors: Silvestri Erica , Tonietto Matteo , Gobbi Susanna , Scelsi Marzia Antonella , Klein Gregory 
Published: January 2025

AbstractBackgroundAmyloid PET imaging enables the simultaneous assessment of both perfusion and amyloid deposition in people with Alzheimer’s Disease (AD) in a single procedure. Perfusion can be derived from kinetic modeling of the full dynamic PET acquisition (i.e., relative blood flow ‐ R1), or more simply as ‘early‐frame’ Standardized Uptake Value Ratio (eSUVR). However, simplified measures could be biased by the amyloid tracer binding to amyloid. Here, we 1) assessed the effect of gantenerumab, an investigational anti‐amyloid monoclonal antibody, on perfusion metrics; 2) tested if the presence of amyloid affects perfusion estimation.MethodFifty‐nine participants underwent dynamic [18F]‐florbetaben PET imaging at baseline and week 116 in the GRADUATE I and II phase III trials of gantenerumab in early AD (NCT03444870, NCT03443973) (Tab. 1). A dual‐time‐window acquisition was employed (0‐30 and 90‐110 mins windows). Perfusion and amyloid load were estimated in: frontal, parietal, temporal, and occipital cortices, and composite neocortex region of interest (ROI), using the cerebellar gray matter as reference region. Perfusion was assessed as R1 using the simplified reference tissue model; and as eSUVR calculating the average activity during the initial 3, 5, or 10 minutes. Amyloid load was computed from the late time‐window as SUVR. Differences in mean perfusion change from baseline between placebo and gantenerumab were tested using a mixed model for repeated measures adjusted for treatment and APOE‐ε4 status. Pearson correlation measured the relationship between amyloid load and perfusion at baseline. All analyses were exploratory in nature and no adjustment for multiplicity was applied.ResultNo treatment effect was observed on R1 in any of the ROIs considered. However, gantenerumab arm resulted in a greater perfusion decrease when using eSUVR, with greater effects observed with longer eSUVR windows. Yet, all perfusion estimates correlated positively with amyloid load, with the correlation strength increasing with longer eSUVR time windows (Fig. 1, Tab. 2).ConclusionPerfusion significantly decreased in both arms, with R1 showing no difference between the two. PET‐derived perfusion metrics correlate positively with amyloid load, indicating amyloid‐dependence. Although kinetic modeling mitigates this bias, it does not fully eliminate it, warranting careful interpretation of these metrics in anti‐amyloid treatment assessments.
Traditional Chinese Medicine for Alzheimer’s Disease: A Systematic Review and Meta‐Analysis
Authors: Chen Yuqing , Zhang Danning , Chen Teng , Wen Lei , Hou Ruihua 
Published: January 2025

AbstractBackgroundThe treatment of Alzheimer’s Disease (AD) remains a challenge for modern medicine due to its complex pathogenesis. Traditional Chinese Medicine (TCM) has accumulated significant value and success in prevention and treatment of diseases, and are regarded as new and promising candidates of AD pharmacological treatments. The current study aimed to systematically evaluate the current evidence base for TCM as a treatment for AD.MethodA systematic search of the literature was performed on electronic databases including PubMed, the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), and Web of Science. Thirteen studies were included in this review, subject to inclusion and exclusion criteria. Screening, data extraction, and quality assessment were undertaken following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. A total of 710 references were identified through searching the databases using the previously described search strategy. After excluding duplicates, titles and abstracts of 596 references were screened; of these, 13 were included in our systematic review and meta‐analysis, and a total of 1,183 participants were randomised. The primary outcome measures for efficacy were cognitive function, measured using the Standardized Mini‐Mental State Examination (MMSE) or ADAS‐cog. Secondary outcome measures included behavioural disturbances measured using the NPI, and activities of daily living assessed using the Alzheimer’s Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL).ResultOur results show a significant improvement of TCM compared to control for cognitive functioning, when measured on both the MMSE and ADAS‐CoG scales. This significant difference did not translate to scores of neuropsychiatric symptoms or ability of daily living activities. We show that TCM has potential to help to slow cognitive decline and improving cognitive function as compared to conventional drug treatment and placebo, but is limited in its effects on psychiatric symptoms and practical activities.ConclusionThese findings highlight TCM as potential adjuvant therapies, with conventional medicine, to improve effectiveness and reduce limitations of conventional AD drug regimes. Studies with larger sample size, rigorous study designs, accurate long‐term reporting, and correlation to neuropathological markers are needed in the future to enhance the evidence base for the use of TCM in AD patients, and to further confirm its efficacy.
VEGFR1‐mediated neuronal cell death following Aß1‐42 oligomers treatment‐ Implications in AD pathogenesis
Authors: Das Pritam 
Published: January 2025

AbstractBackgroundRecent transcriptome analysis has demonstrated increased expression of Vascular Endothelial Growth Factor receptor‐1 (VEGFR‐1/FLT1) and decreased expression of VEGFR‐2/KDR in AD brain. Increased expression of VEGFR‐1 and its ligand VEGFB were associated with a more rapid rate of cognitive decline, providing evidence of a potential link between aberrant VEGFR‐1 expression in AD pathogenesis. In this study, we explored the potential role of aberrant VEGFR‐1 expression in neurons on AD pathology.MethodTo confirm VEGFR‐1 expression in AD brains, we performed immunostaining in AD brain sections (AD n = 5 (Braak stage V‐VI, and normal controls n = 5 Braak 0‐II) in AD brains. To determine a potential detrimental role of neuronal VEGFR‐1 expression on AD associated pathologies, we exposed SH‐SY5Y human neuroblastoma cells and mouse primary neurons to either hypoxia conditions (1%O2) or 5uM Aß 1‐42 oligomers for 72hrs.ResultWe found increased VEGFR‐1 immunoreactivity in dystrophic neurites in the vicinity of Thio‐S positive “cored” amyloid plaques, whereas VEGFR‐2 antibody staining showed minimal neuronal staining in AD samples. And treatment with hypoxia or Aß oligomers both in SH‐SY5Y cells and mouse primary neurons showed increased VEGFR‐1 expression and cleaved caspase 3 activation, leading to neuronal cell death. Significantly, siRNA mediated knockout of VEGFR‐1 in the neurons prevented both hypoxia and Aß oligomer induced cell death. We also show that treatment with either hypoxia or Aß oligomers reduced mRNA expression of cell survival genes including Hippo pathway YAP1 and VEGFR‐2, and siRNA mediated VEGFR‐1 knockdown normalized both YAP1 and VEGFR‐2 levels. Significantly, over‐expression of the VEGFR‐1 by itself reduced mRNA expression of YAP1 and VEGFR‐2 and readily induced neuronal cell death, implicating the VEGFR‐1/VEGFR‐2/YAP1 signaling axis in hypoxia and Aß oligomer induced neuronal cell death, which is a novel finding.ConclusionThese results demonstrate that VEGFR‐1 may play an important transcriptional regulatory role in neuronal cell survival responses and suggest that modulating VEGFR‐1 expression and signaling could have beneficial effects in AD pathogenesis.
The role of TLR4/MyD88 signaling in systemic inflammation in an Alzheimer mouse model
Authors: Yang Junling , Fukuchi Ken‐ichiro 
Published: January 2025

AbstractBackgroundMany lines of evidence support that systemic inflammation promotes Alzheimer’s disease (AD) progression. Amyloid plaques are closely accompanied with neuroinflammation characterized by activated microglia and reactive astrocytes. Aging is the largest known risk factor for AD and is characterized by chronic, systemic, low‐grade inflammation (inflamm‐aging). However, the precise molecular mechanisms by which chronic, systemic inflammation contributes to development of AD remain to be elucidated. In order to investigate the role of TLR/MyD88 signaling in chronic, systemic, low‐grade inflammation associated with development of AD, an AD mouse model (TgAPP/PS1) with MyD88+/+ (wild‐type) or MyD88± (MyD88 heterozygous: one allele is deleted) was treated with low dose lipopolysaccharide (LPS) for 3 months.MethodWe treated 6‐month‐old female MyD88+/+ TgAPP/PS1 and MyD88± TgAPP/PS1 mice with LPS (0.5 mg/Kg/weekly intraperitoneal injection) or PBS for 3 months and, then, performed a battery of behavioral tests including open‐field, T‐maze, elevated plus‐maze, and Morris water maze (n = 6‐7/group).ResultIn the open‐field, LPS‐treated MyD88± TgAPP/PS1 mice spent more time in the periphery (P<0.05) and tended to spend less time in the center of the open‐field, suggesting increased anxiety. In the acquisition phase of Morris water maze, there were significant day effects for path lengths (F (4, 84) = 24.66, P< 0.001) and escape latencies (F (4, 84) = 23.39, P < 0.001) caused by a reduction in both values over days in all 4 groups. There were no intergroup differences in the path lengths and the latencies. In the probe trial, the percentages of time spent in the correct quadrant for LPS‐treated MyD88+/+ TgAPP/PS1 mice were significantly greater than any other groups (F (3, 21) = 5.46, P<0.01). There were no intergroup differences in the visible platform subtask.ConclusionSurprisingly, chronic and systemic LPS treatment improved memory only in MyD88+/+ TgAPP/PS1 mice but not in MyD88± TgAPP/PS1 mice. We are currently investigating pathological and biochemical changes in these experimental animals.
Fiber tract profiles of community dwelling older adults with LATE‐NC and associations with postmortem TDP‐43
Authors: Heywood Ashley , Schneider Julie A. , Bennett David A. , Arfanakis Konstantinos , Wang Lei 
Published: January 2025

AbstractBackgroundTAR DNA‐binding protein 43 (TDP‐43), has been shown to be involved in various neurodegenerative disorders involving axonal damage including ALS, FTLD, and LATE. Studying the relationships between postmortem TDP‐43 and antemortem white matter (WM) structural integrity can allow for a better understanding of underlying neural mechanisms of the disease. Measures of white matter integrity assume fiber bundles to maintain similar characteristics along the length of the tract, however, advanced computational research has identified that white matter integrity varies in stereotyped patterns along the tract.MethodsIn‐vivo diffusion‐weighted images were gathered on a 1.5T scanner from subjects from the Religious Orders Study and the Rush Memory and Aging Project. Tractography was conducted for each subject using Mrtrix3 and Automated Fiber Quantification (AFQ) was used to calculate fractional anisotropy (FA) along fiber tracts for 20 major fiber bundles. A semi‐quantitative rating of TDP‐43 severity was assessed in 5 brain regions. We utilized regression models to relate postmortem disease and antemortem FA at 100 nodes along each fiber tract while controlling for coexisting Alzheimer’s disease pathology and demographics.ResultsThe 63 subjects were 91.2 (SD = 6.2) [range: 71.7‐103.6] years old at death. Thirty‐eight percent had TDP‐43 pathology and 36% had cognitive changes before death. Overall, fiber tract profiles revealed variation of FA along each fiber bundle. Results measuring the relationship to disease revealed a significant negative relationship (FWE corrected‐p<0.05) between postmortem TDP‐43 and FA at unique portions of the left hippocampal cingulum.ConclusionFindings support current literature indicating white matter integrity does not follow a uniform pattern along fiber tracts in older adults. Pathology relationships reveal unique portions of tracts which have unique relationships to TDP‐43. Understanding the relationship between disease and these vulnerable regions will be critical in elucidating the effect of TDP‐43 on white matter integrity leading to cognitive decline.
Deciphering the pathological significance of self‐propagating Aβ strains in different animal models
Authors: Morales Rodrigo 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is an heterogenous disorder characterized by the accumulation of amyloid‐beta (Aβ) and tau. One possible explanation for the clinical and pathological variation in AD lies in the presence of distinct conformational strains of Aβ. Numerous studies provide compelling evidence for the existence of such strains as well as their ability to template their conformations in a prion‐like manner. However, the interaction of such Aβ strains with different hosts has yet to be thoroughly examined. Here, we examined the host‐seed interaction of different human brain‐derived and synthetic misfolded Aβ strains in two different mouse models of amyloid pathology. We specifically explored the potential differences in amyloid propagation and pathological manifestations considering Aβ strains and animal models as variables.Method50‐day‐old Tg2576 mice were intra‐cerebrally challenged with mouse or human brain‐derived Aβ seeds, or synthetic Aβ strains. Age‐matched APP/PS1 mice were intra‐cerebrally challenged with the biological Aβ seeds as well. Cerebral pathology was assessed in 300‐day‐old Tg2576 mice, and in 180‐day‐old APP/PS1 mice.ResultTwo structurally defined synthetic misfolded Aβ strains induced remarkably different pathological features in Tg2576, including different rates of aggregation, tropism to specific brain regions, and differential recruitment of Aβ40/Aβ42 peptides. Moreover, the administration of human brain homogenates derived from AD patients, displaying unique patterns of amyloidosis, seeded distinct phenotypes in challenged APP/PS1 mice, as evaluated by their seeding activity, vascular pathology, and reactivity to thioflavin‐S. Finally, we observed that the same human brain homogenate induced a different cerebral Aβ pathology when inoculated into Tg2576 and APP/PS1 mice.ConclusionOur findings support the concept of Aβ strains and demonstrate that they may drive different clinical and pathological outcomes in humans. Our work highlights the contribution of the host in pathological characteristics. Future research could lead to successful personalized diagnostic approaches and treatments.
Disease trajectories before dementia: Evidence from a large‐scale community‐based prospective study
Authors: Li Jialin , Xia Ding , Cui Mei , Wang Yingzhe , Li Jincheng , Jin Li , Chen Xingdong , Suo Chen , Jiang Yanfeng 
Published: January 2025

AbstractBackgroundDementia patients often have several co‐existing diseases, whereas the specific temporality and development patterns between them remain uncertain.MethodBased on the multicenter, community‐based prospective UK Biobank, enriched disease diagnoses were extracted from hospital admission linkage, along with basic demographic information and individual genome data from the baseline visit. We constructed disease trajectory before dementia utilizing the phenome‐wide association analysis to firstly filter potential precursors, the directional test to select temporal disease pairs, and conditional logistic regression to finally quantify association strength. Disease trajectory was also constructed across diverse subpopulations stratified by dementia subtypes (Alzheimer’s disease and vascular dementia), sex, median diagnosis age, and Apolipoprotein E (ApoE) ε4 status (carrier or not), respectively. Mendelian randomization (MR) was further adopted to suggest causality for longitudinal associations.ResultOur study comprised 434,266 participants without baseline dementia and 4,638 individuals with all‐cause dementia, with a median follow‐up of 10.9 years. Initially, 1,253 diseases were extracted as potential nodes of disease trajectory preceding dementia. We ultimately defined three clusters of disease trajectory preceding all‐cause dementia, initiated by circulatory, metabolic, and respiratory system diseases (Figure 1). The initial diseases in the trajectory were diagnosed approximately 5‐15 years before dementia. Cerebral infarction or chronic renal failure following chronic ischemic heart disease was the specific trajectory before vascular dementia. Angina, progressing to atrial fibrillation and then dementia, is a key trajectory in males, senior dementia patients, and ApoE ε4 non‐carriers. Dementia patients without ApoE ε4 typically developed urinary system disorders after musculoskeletal and connective tissue diseases. Lipid metabolism disorders remained in trajectories across all subgroups. However, MR based on inverse variance weighting indicated a modest causal relationship between lipid disorder and Alzheimer’s disease (Odds ratio = 1.05, P value = 0.234).ConclusionThis study offers a comprehensive view of longitudinal disease trajectories before dementia among diverse subpopulations, indicating critical precursor diseases and specific development patterns. The findings emphasize the importance of clinical attention to patients with cardiometabolic dysfunction in midlife for screening and prevention of dementia. Further population studies and mechanism explorations are needed to validate and generalize the trajectories.