bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral tributyrin supplementation attenuates Alzheimer’s disease‐associated neuropathology and prevents cognitive and behavioral deficits in the 3xTg‐AD mouse model
Authors: Chilton Paula M. , Ghare Smita S. , Charpentier Benjamin T , Myers Scott A. , Rao Aakarsha V. , Greenwell J Caleb , Tyagi Neetu , Behera Jyotirmaya , Wang Yali , Sloan Lucy J , Zhang JingWen , Gobejishvili Leila , Whittemore Scott R , Shields Christopher B , Cooper Gregory , McClain Craig J. , Barve Shirish 
Published: December 2023

AbstractBackgroundDysbiosis of the gut microbiome is associated with various diseases, including Alzheimer’s Disease (AD). A decrease in intestinal butyrate‐producing bacteria has been indicated by pre‐clinical and clinical studies in AD; therefore, we assessed the effects of long‐term oral administration of tributyrin (TB: a butyrate pro‐drug) on the development of memory and neuromuscular deficits, and CNS pathology in 3xTg‐AD (3xTg) mice.MethodOral gavage with tributyrin (2 mg/kg) was given twice weekly to female 3xTg mice between 6‐ and 17‐months of age. Treatment was stopped and mice were tested for spatial memory (Y‐maze and novel object recognition test‐NORT) and neuromuscular function (RotaRod and grip tests). Brains from untreated (2‐, 12‐, or 18‐month‐old untreated or TB treated 18‐month‐old mice were formalin‐fixed, paraffin‐embedded for microscopic analysis of AD‐associated pathology, neuroinflammation, and oxidative stress markers.ResultShort‐term, episodic memory and spatial memory along with balance and coordination and grip strength were all significantly decreased in untreated 3xTg mice at 17‐months of age compared to 2‐ or 10‐month‐old mice. TB treatment, however, attenuated these effects in 17‐month mice. TB treatment did not affect the accumulation of either Aβ or Tau in the subiculum at 18‐months. However, pTau hyperphosphorylation—as indicated by co‐staining with both pTau(Ser404) and AT‐8 pTau (Ser202/Thr205) mAb—was effectively prevented with TB treatment. Similarly, significant age‐dependent neuroinflammation indicated by IBA1 (microglia) and GFAP (astrocytes) staining was increased in the hippocampus of 18‐month 3xTg mice and was effectively prevented by TB treatment. Additionally, markers of oxidative stress, 4‐HNE and acrolein adducts, were also increased in the molecular layer of the hippocampus and attenuated in TB treated mice.ConclusionThese studies demonstrate that TB treatment after initiation of Aβ deposition in the subiculum dramatically abrogates the loss of neurologic function in 3xTg mice as demonstrated by increased memory, cognition, and neuromuscular function. Moreover, these increases coincide with attenuated AD‐associated pathology in the hippocampus of TB‐treated 3xTg mice. Importantly, these data indicate that treatment with a butyrate pro‐drug can be integrated into treatment strategies to preserve cognitive and neuromuscular functions in patients in the prodromal phase of AD.
EEG‐based neural biomarker for diagnosis and assessment of mild cognitive impairment and Alzheimer’s disease
Authors: Jiao Bin , Li Rihui , Tang Beisha , Shen Lu 
Published: December 2023

AbstractBackgroundElectroencephalogram (EEG) has emerged as a non‐invasive tool to detect the aberrant neuronal activity related to different stages of Alzheimer’s disease (AD). However, the effectiveness of EEG in the precise diagnosis and prediction of AD and its preclinical stage, mild cognitive impairment (MCI), has yet to be fully elucidated. In this study, we aimed to identify key EEG biomarkers that are effective in distinguishing patients at the early stage of AD and monitoring the progression of AD.MethodA total of 890 participants, including 189 patients with MCI, 330 patients with AD, 125 patients with other dementias (frontotemporal dementia, dementia with Lewy bodies, and vascular cognitive impairment), and 246 healthy controls (HC) were enrolled. Biomarkers were extracted from resting‐state EEG recordings for a three‐level classification of HC, MCI, and AD. The optimal EEG biomarkers were then identified based on the classification performance. Random forest regression was used to train a series of predictive models by combining participants’ EEG biomarkers, demographic information (i.e., sex, age), CSF biomarkers, and APOE phenotype for predicting the disease progression and individual’s cognitive function.ResultThe identified EEG biomarkers achieved over 70% accuracy in the three‐level classification of HC, MCI, and AD. Among all six groups, the most prominent effects of AD‐linked neurodegeneration on EEG metrics were localized at parieto‐occipital regions. Noteworthy, the absolute theta power of channel O2 was negatively correlated with Aβ42 (r = ‐0.358, p < 0.001) and positively correlated with p‐tau (r = 0.442, p < 0.001). In terms of cognitive assessment, the Hjorth mobility of channel O1, O2 and P4 were found to be positively associated with MMSE and MoCA scores (r = 0.416‐0.464, all p < 0.001). In the predictive analyses, the optimal EEG features were more effective than the CSF + APOE biomarkers in predicting the age of onset and disease course, whereas the combination of EEG + CSF + APOE measures achieved the best performance for all targets of prediction.ConclusionOur study indicates that EEG can be used as a useful screening tool for the diagnosis and disease progression evaluation of MCI and AD.
Time for Living & Caring: An Online Intervention to Support Dementia Caregivers’ Use of Respite
Authors: Utz Rebecca , Thompson Amber , Wong Bob , Iacob Eli , Sparks Catharine , Terrill Alexandra , Caserta Michael 
Published: December 2023

AbstractBackgroundBecause of the demanding care needs associated with dementia, family caregivers often have increasing anxiety and burden over time. Respite, defined as time away from caregiving, is the most requested type of caregiver support and is hypothesized to benefit caregiver wellbeing. However, many caregivers report low respite satisfaction, feeling as though they wasted their time or that they did not know how to use their respite time in a way that benefited them.MethodTime for Living and Caring (TLC) is a virtual coaching “app” that helps caregivers schedule and plan their respite time. With funding support from NIA (R01‐AG061946), we conducted a pilot test with dementia caregivers (n = 159), randomized into one of two delivery methods – an immediate group that could access all features and functions of the app for 16 weeks, and a delayed‐attention group that received initial instructions on calendaring for 8 weeks and then the more interactive coaching features during the second 8 weeks. This additive “dosing” model where the immediate group received “2 doses” in the first 8 weeks while the delayed‐attention group got “1 dose” initially and “1 dose” during weeks 8‐16 was evaluated using generalized linear modeling on caregiver‐reported anxiety and burden levels over time.ResultsBoth immediate and delayed‐attention groups reported 1) increased respite time, 2) increased respite satisfaction, and 3) felt that they were better caregivers because of respite. At 8 weeks, the immediate group did not change in anxiety while the delayed group worsened (p < 0.001). At 16 weeks, the groups were similar in their anxiety levels. By the 20‐week follow‐up period, when neither group had access to TLC, both groups were worsening in their anxiety. Caregiver burden worsened at 16 weeks for the immediate group.ConclusionTLC shows potential as an intervention model to improve respite quality and minimize increases in anxiety and burden over time. Intervention delivery that provides additional features or instructions after the initial orientation may keep participants more engaged and result in better caregiver outcomes over time, compared to providing the full set of online resources all at once.
Correlations between daily activities and the Korean‐Everyday cognition, and the Gottfreis‐Bråne‐Steen scale in the patient complaint with cognitive decline
Authors: Lee Juyoun , Lee Ae Young 
Published: December 2023

AbstractBackgroundTo get the right diagnosis of dementia, clinicians need a wealth of information from the patient and their caregivers, as well as objective examinations. Some questionnaires may provide sufficient information to be obtained by interviewing. The Everyday Cognition (ECog), and the Gottfreis‐Bråne‐Steen (GBS) scale were developed to measure functional changes in cognitive decline patients through the caregiver’s report. This study aims to evaluate the usefulness of theses scales in the dementia clinic.MethodThe Korean‐ECog (K‐ECog), and GBS scale was answered by 100 caregivers from patients with cognitive decline. Results of neuropsychological tests, and clinical information were collected. Correlation analyses were conducted between K‐ECog, GBS, Korean version of instrumental activities of daily living (K‐IADL), Clinical dementia rating‐sum of boxes (CDR‐SB), global deterioration scale, and other detailed cognitive tests.ResultThis study included 97 patients, including 54 dementia, 34 mild cognitive impairment, and 9 subjective memory impairment. The K‐ECog, and GBS had moderate correlations with K‐IADL, and CDR‐SB. The K‐ECog and GBS had strong correlation each other. And GBS score was effectively differentiated dementia patients from non‐demented patients, respectively.ConclusionThe two scales, the K‐ECog, and GBS, are well represented cognitive dysfunctions of the daily activities in the patients with cognitive decline, as with the K‐IADL, CDR‐SB. Therefore, these scales can make it easier to understand the patient’s daily cognitive state and diagnose the disease relatively quickly and with little effort.
Global analysis of synapse‐enriched miRNA in Alzheimer’s disease temporal cortex post‐mortem
Authors: Gil Laia Lidón , Núñez‐Llaves Raúl , Perlaza Danna , Cervantes‐González Alba , Tamayo Natalia Valle , Serrano‐Requena Sara , Dolcet Sònia Sirisi , Sánchez‐Aced Érika , Iulita Maria Florencia , Dols‐Icardo Oriol , Lleó Alberto , Pérez‐González Rocío , Belbin Olivia 
Published: December 2023

AbstractBackgroundSynapse loss is the major neuropathologic correlate of cognitive impairment in Alzheimer’s disease (AD). MicroRNA (miRNA) regulate synaptic plasticity and play a role in AD pathogenesis and therefore represent potential therapeutic targets. The aim of this study is to determine the role of miRNA‐mediated dysfunction at AD synapses.MethodWe prepared homogenates (H) and synaptosomes (SYN) from frozen post‐mortem temporal cortex tissue from 10 AD (mean age = 77.4±4.2) and 10 non‐pathological controls (CN; mean age = 72.3±5.9). We extracted (mirVana) and quantified miRNA using the TaqManR Advanced miRNA Assay, QuantstudioTM and OpenarrayTM system. Samples were normalized (median Ct). DeltaCt values calculated relative to control hsa‐miR‐16‐5p. We performed linear regression to identify differentially expressed (DE) miRNA across groups, controlling the false discovery rate (FDR) using the Benjamini‐Hochberg method. We considered DE miRNA with fold changes <0.8 or >1.2 (adj.p<0.05) in AD vs CN. We searched two predictive databases (TargetScan and miRDB) for gene targets of the DE miRNA and identified overrepresented target genes using the Panther database (PantherDB.org) after controlling the FDR.ResultOf the 751 miRNA included on the Openarray, we detected 411 in H and 432 in SYN, with 89% overlap between AD and CN in SYN. To enrich our analyses for miRNA that are predominantly present at the synapse, we took forward only the 47 miRNA with >1.2‐foldchange (adj.p<0.2) in SYN vs H in either AD or CN. miR‐132‐3p and miR‐132‐5p were under‐expressed (0.17‐fold, p = 0.001 and 0.35‐fold, p = 0.006, respectively) and miR‐181a‐3p was over‐expressed (2.13‐fold, p = 0.04) in AD compared to CN SYN. The 594 gene targets of upregulated synaptic miRNA (miR‐181a‐3p) were overrepresented in pathways regulating synaptic function and mitochondrial bioenergetics and integrity. The 474 and 1230 targets of downregulated synaptic miRNA (miR‐132‐3p and miR‐132‐5p, respectively) were overrepresented in the same pathways as well as pathways related to interleukin production, tau pathology, Abeta production, apoptotic signalling and oxidative stress.ConclusionThree synapse‐specific miRNA are differentially expressed at AD synapses and target genes involved in core AD‐related processes, thus making them promising therapeutic targets. Future studies will seek to validate these findings and determine the specificity for AD over other neurodegenerative diseases.
Two‐stage diffusion model deriving FDG‐PET from T1 Weighted Magnetic Resonance Images for diagnosis of Alzheimer’s disease
Authors: CHEN Ke , Hosseini Akram A. , Weng Ying , Dening Tom , Zuo Guokun 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) is a neurodegenerative disease which is characterized by cognitive and functional impairment, and defined by triad of Amyloid status, Tau pathology, and Neuroimaging marker of neurodegeneration or neuronal injury. An early diagnosis of AD can be challenging and it can be detected earlier in brain functional imaging than brain structural imaging.MethodWe develop a pipeline for synthesizing FDG‐PET/MRI from source MRI‐T1‐Weighted (MRI‐T1W) images based on denoising diffusion mechanism [1]. The pipeline includes a forward pass which encodes the source MRI‐T1WI images to gaussian noise space, and a backward pass which generates the corresponding FDG‐PET from the derived noises with repeated denoising steps. Furthermore, to validate the effectiveness of the synthesized FDG‐PET images, we also develop multiple types of classifiers and the experiments for both single input of MRI‐T1WI and joint input of MRI‐T1WI and synthesized FDG‐PET.ResultThe experiments are performed on 1036 of FDG‐PET/MRI pairs (286,474, 276 for Cognitive Normal, Mild Cognitive Impaiement and Alzheimer’s Disease each) are obtained from ADNI [2] datasets and display the promising results with low Mean Absolute Error (MAE) and high Structural Similarity Index Measure (SSIM) for the two stage diffusion denoising based FDG‐PET synthesis pipeline. The results for the additional classification experiments also show that in most cases the joint input enhances the classifiers' performance in accuracy and F1‐score. The results also indicate that the synthesized FDG‐PET images are not only visually similar to the ground truth images, but also improve the performance of machine learning based AD diagnosis.ConclusionThis work provides support for the notion that machine learning‐derived image analysis may be a useful approach to improving the diagnosis of AD.Reference:[1] Ho, J., Jain, A., & Abbeel, P. (2020). Denoising diffusion probabilistic models. Advances in Neural Information Processing Systems, 33, 6840‐6851.[2] Petersen, R., Aisen, P. S., Beckett, L. A., Donohue, M. C., Gamst, A. C., Harvey, D. J., … & Toga, A. W. (2010). Alzheimer’s disease neuroimaging initiative (ADNI). Neurology, 74(3), 201‐209.
Association of white matter hyperintensity burden and cognitive performance in young‐aged, middle‐aged and old‐aged participants: Results of the population‐based 1000BRAINS study
Authors: Jokisch Martha , Schramm Sara , Jockwitz Christiane , Caspers Svenja , Jöckel Karl‐Heinz , Erbel Raimund , Weimar Christian , Hermann Dirk , Gronewold Janine ,   the Heinz Nixdorf Recall Study Investigative Group
Published: December 2023

AbstractBackgroundSome individuals seem less susceptible to the effect of high white matter hyperintensity (WMH) load on cognition reflecting differences in individual cognitive reserve (CR). Little is known about young‐ or middle‐aged participants. The aim of the present study was to examine (1) the effect of WMH on global cognition in three different age groups and (2) if education (as proxy for CR) moderates this association.MethodWe included 707 healthy participants (18‐85 years) without evidence of cardiovascular/neurological disease (young‐aged: 18‐44 years (Ø33.5±6.7): n = 108; middle‐aged: 45‐65 years (Ø57.9±5.5): n = 341; old‐aged: >65 years (Ø72.0±4.1): n = 258) from the population‐based 1000BRAINS study. An extensive cognitive assessment was conducted. The sum of all cognitive domain z‐scores defined the global score. Education was classified according to the International Standard Classification of Education as total years of formal education, combining school and vocational training. Magnetic resonance imaging (MRI) was carried out on a 3‐Tesla‐MR‐scanner (Tim‐TRIO, Siemens Medical Systems, Erlangen, Germany). WMH volume was determined using the Brain‐Intensity‐Abnormality‐Classification‐Algorithm. The associations of global cognition as outcome with WMH volume (in cm3) as predictor were analyzed using linear models (PROCESS v4.1 macro for SPPS) stratified by age group resulting in regression coefficient b with 95% confidence intervals (CI; adjusted for age, sex, depression, diabetes mellitus). To examine moderation effects of education, all models contained an interaction term (WMH x education).ResultHigher WMH volume was associated with lower global cognition in middle‐aged participants (b:‐0.27 (‐0.52 to ‐0.03, all reported results are fully adjusted). This effect was moderated by education (interaction term: b:‐0.07 (‐0.014 to ‐0.01)). In the young‐aged group, the association between WMH load and cognition was ‐1.27 (‐3.30 to 0.77). No association was found in the old‐aged group (b: ‐0.03 (‐0.20 to 0.14)).ConclusionHigher WMH load was associated with lower cognitive performance only in middle‐aged participants and was moderated to a small degree by education. Overall, the influence of WMH on global cognition in our cohort of healthy participants seems limited. Future analyses will focus on specific cognitive domains that might be more vulnerable to higher WMH load and will examine participants with certain cardiovascular risk profile.
Association of creatine kinase with cognition, neuroimaging, and Alzheimer’s pathology
Authors: Wang Yu‐tong , Gao Pei‐yang 
Published: December 2023

AbstractBackgroundCreatine kinase (CK) and its related metabolites are known to imply cardiovascular system disease, whereas the cardiovascular metabolic state is associated with the state of cognitive well‐being of the brain. However, the extent to which CK levels is related with cognitive impairment has not been revealed.MethodThe Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were used for this study. We first investigated the intergroup difference of participants demographic, cognitive status, Alzheimer’s disease (AD) diagnosis, and cerebrospinal fluid (CSF) AD pathology biomarkers. Next, we conducted to use liner regression model to examine the association of CK with CSF AD pathology biomarkers, cognition, and brain structure. Last, mediation analyses were utilized to explore whether the association between CK and cognition were mediated by CSF AD pathology biomarkers.ResultA total of 1,607 participants (mean age were 73.82±7.23 and 55.76% were male) from the ADNI database were involved in this cross‐sectional study. We found a significant difference through age, gender, AD diagnosis, and cognitive status subgroups in intergroup difference analysis (P<0.05). Meanwhile, significant association of lower level of CK with decreased level of β‐amyloid1‐42 (Aβ; β = 0.069, P = 0.040) and increased level of phosphorylated tau (P‐tau; β = ‐0.084, P = 0.007), and total‐tau (T‐tau; β = ‐0.071, P = 0.021), respectively. Liner regression analysis also indicated that the lower level of CK was associated with worse cognition (Mini‐Mental State Examination: β = 0.059, P = 0.021; Alzheimer’s Disease Assessment Scale: β = ‐0.065, P = 0.012), however not to brain structure. Moreover, mediation analysis identified CSF AD pathology biomarkers mediated the association between level of CK and cognition.ConclusionOur findings offered detailed proof to advise that the lower level of CK was significantly associated with poor cognition and it might be mediated by CSF AD pathology biomarkers. For future research, it is necessary to identify the precise reason and process by which changed levels of CK impact cognition.
Analytical and clinical validation of a progranulin ELISA in the FTD disease spectrum
Authors: Meda Francisco , Simrén Joel , Archetti Silvana , Cantoni Valentina , Andreasson Ulf , Blennow Kaj , Borroni Barbara , Kvartsberg Hlin , Zetterberg Henrik 
Published: December 2023

AbstractBackgroundThe granulin gene (GRN) encodes for the glycoprotein progranulin (PGRN) which is involved in lysosomal function and homeostasis. Heterozygous mutations in this gene lead to PGRN haploinsufficiency and are usually associated with genetic frontotemporal dementia (FTD) (Holler et al., 2017). FTD is a diverse neurodegenerative disease with distinct phenotypes. It is considered the second most common form of early onset dementia, after Alzheimer’s disease (AD), and is characterized by protein aggregation, neurodegeneration and lysosomal dysfunction (Greaves et al., 2019). In this study, we aimed to perform analytical and clinical validation of a commercial progranulin kit (Adipogen Life Sciences) for clinical use.MethodAnalytical validation was carried out by testing assay precision, selectivity, measurement range, dilution linearity, interferences and sample stability using de‐identified plasma samples according to previously described procedures (Andreasson et al., 2015). For clinical validation, PGRN levels were measured in plasma from 32 cognitively healthy individuals, 52 confirmed GRN mutation carriers (GRN+ symptomatic, n = 31; GRN+ pre‐symptomatic, n = 21), 25 C9orf72 mutation carriers (C9orf72+ symptomatic, n = 20; C9orf72+ pre‐symptomatic, n = 5) and 216 patients with different neurodegenerative diseases (AD n = 64; behavioral variant FTD n = 64, primary progressive aphasia n = 46, corticobasal syndrome n = 24, progressive supranuclear palsy n = 18) of which 70 were confirmed as non‐mutation carriers.ResultAmong the analytical validation parameters, assay precision indicated an inter‐plate coefficient of variance <7%, selectivity with an average value of 96% spike recovery, measurement range 6.25‐400 ng/mL and linearity range from 1:50 to 1:200 dilution. Hemolysis did not interfere with progranulin measurement and progranulin levels were resistant to freeze/thaw cycles and storage at different temperatures. For the clinical validation, this assay is capable of distinguishing GRN mutation carriers from controls and non‐GRN mutation carriers with very good sensitivity and specificity and established cut‐off at 51 ng/mL (97%, 98%, respectively).ConclusionIn this study, we demonstrate robust analytical and diagnostic performance of this commercial progranulin kit for implementation in clinical routine. This allows a straightforward screening of patients to identify individuals who are GRN mutation carriers and thus, likely improve clinical management. This assay might also be used to evaluate the effect of novel PGRN‐targeting drugs and therapies.