bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visit‐to‐visit blood pressure variability and medial temporal perfusion in APOE e4 homozygotes
Authors: Sible Isabel J , Nation Daniel A. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundBlood pressure variability (BPV), independent of traditionally studied/targeted average blood pressure levels, is an emerging risk factor for cognitive impairment and Alzheimer’s dementia, possibly through links with cerebrovascular disease. Recent studies suggest vulnerability of the medial temporal lobes to tau accumulation and atrophy among individuals with elevated BPV, especially older APOE e4 carriers. Increased BPV has also been linked with lower cerebral blood flow (CBF) and perfusion decline in medial temporal regions, but it remains unclear how BPV and APOE e4 may interact to influence CBF. The aim of the current study was to determine whether the relationship between BPV and medial temporal lobe CBF varies by APOE e4 dose in older adults without dementia.Method105 older adults without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent 3‐4 blood pressure measurements between study baseline and 12‐months follow‐up and arterial spin labeling (ASL)‐MRI at 12‐months follow‐up or later (range: 0 – 84 months). Visit‐to‐visit BPV was calculated as variability independent of mean. CBF was determined for medial temporal regions (residualized by precentral [reference region] CBF), including hippocampus, parahippocampal gyrus, and entorhinal cortex. Venipuncture determined APOE e4 allele count (0 alleles: n = 71; 1 allele: n = 28; 2 alleles: n = 6). Multiple linear regression examined the interaction of BPV x APOE e4 dose on medial temporal CBF, controlling for age, sex, race/ethnicity, antihypertensive use, mean blood pressure, and cerebral metabolism (FDG‐PET).ResultElevated BPV was associated with lower CBF in entorhinal cortex (ß = ‐.96 [‐1.62, ‐.31]; p = .005) and parahippocampal gyrus (ß = ‐.63 [‐1.26, ‐.0002]; p = .049) in individuals with 2 APOE e4 alleles, whereas BPV was not significantly associated with CBF in these regions in individuals with 0 or 1 APOE e4 alleles (p’s > = .08). There was no significant interaction of BPV x APOE e4 dose on hippocampal CBF.ConclusionHigher BPV is associated with lower medial temporal CBF in APOE e4/e4 carriers, suggesting BPV may be an understudied vascular risk factor for those at greatest genetic risk for Alzheimer’s disease, with potential therapeutic implications.
In vivo tau is associated with retrospective change in memory and processing speed, but not reasoning, in cognitively unimpaired older adults.
Authors: Simon Sharon Sanz , Varangis Eleanna , Lee Seonjoo , Gu Yian , Gazes Yunglin , Habeck Christian , Stern Yaakov 
Published: December 2023

AbstractBackgroundThe relationship between tau accumulation and cognitive decline in cognitively unimpaired older adults is still unclear. The tau PET tracer 18F‐MK‐6240 has shown favorable imaging carachteristics to identify early tau accumulation in older adults.MethodWe evaluated the relationship between in vivo tau levels (18F‐MK‐6240) and retrospective cognitive change over 5 years in episodic memory, processing speed, and reasoning. For tau quantification, we created a set of regions of Interest (ROIs), selected a priori based on previous literature: 1) Total‐ROIs comprising all 16 areas selected; 2) Medial Temporal Lobe‐ROI, 3) Lateral Temporal Lobe‐ROI and Cingulate/Parietal lobel‐ROI.Result41 cognitively unimpaired older adults was included in the study, 82% classified as amyloid‐b negative. Higher tau burden in most meta‐ROIs was associated with steeper decline in memory and speed. There were no associations between tau and reasoning change.ConclusionOur finding reforces the notion that early tau accumulation in areas related tio Alzheimer’s disease is associated with cognitive decline in cognitively unimpaired individuals, even in a sample characterized with low amyloid‐b pathology. The novel contributin of this work is the relevante of tau accumulation beyond memory, particularly in processing speed decline.
Metabolites and 12‐Year Cognitive Measures Among a Cohort of Boston Area Puerto Ricans
Authors: Palacios Natalia 
Published: December 2023

AbstractBackgroundRecent studies have identified plasma metabolites associated with cognitive decline and Alzheimer’s disease; however, little research on this topic has been conducted in Latinos, especially Puerto Ricans. This study aims to add to the growing body of metabolomics research in Latinos to better understand and improve the health of this population.MethodWe assessed the association between plasma metabolites and global cognition, as well as memory and executive function component scores, over 12 y of follow‐up in 736 participants of the Boston Puerto Rican Health Study (BPRHS). Metabolites were measured with untargeted metabolomic profiling (Metabolon, Inc) at baseline. We used covariable adjusted linear mixed models (LMM) with a metabolite*time interaction term to identify metabolites (of 621 measured) associated with ∼12y cognitive trajectory.ResultWe observed strong inverse associations between medium‐chain fatty acids, caproic acid, and the dicarboxylic acids, azelaic and sebacic acid, with global cognition and memory. Metabolites on the tyrosine and tryptophan pathways as well as several phospholipids, were associated with improvement in cognitive trajectory. We also observed an association between glucose and taurocholate, a primary bile acid, and worse executive function trajectory.ConclusionThe metabolites identified in this study are generally consistent with prior literature and highlight a role for tryptophan, bile acid, branched chain amino acid, phospholipid and glucose metabolism in cognitive decline.
Anti‐MS4A4A Antibody Modulates Myeloid Cell Biology and TREM2 Signaling
Authors: Lightfoot Yaima Luzardo , Botte Alexandra , Trinh Ronnie The Pong , Ding Grant S. , McReynolds Morgan , Allen Jason K. , Gonzalez Michelle A , Shi Chunchua , Molldrem Jeffrey J. , Heffernan Timothy P. , Lofton Timothy E , Münch Alexandra , Marcora Edoardo , Goate Alison , Ray William J 
Published: December 2023

AbstractBackgroundGenome‐wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) within the membrane‐spanning 4‐domains subfamily A (MS4A) gene locus are linked with protection from Alzheimer’s Disease (AD) risk, delayed age‐at‐onset, and reduced expression of MS4A4A and MS4A6A in myeloid cells. Recently, protective variants within the MS4A gene region have been associated with increased levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Despite these associations, the pathophysiological role(s) of MS4A family members in AD remain understudied. MS4A proteins have been reported to modulate immune cell activation by regulating calcium exchange and the signaling of other immunoreceptors. Therefore, targeting these cell membrane proteins with antibodies that mimic the aforementioned gene signatures may lead to a functional microglial state that is protective in AD.MethodMS4A4A was overexpressed in HEK293 and HEK293/TREM2+DAP12 cells to measure impact of MS4A4A on calcium flux and TREM2 signaling, respectively. An antibody targeting human MS4A4A was developed and used to treat primary human macrophages in vitro. Cellular localization of MS4A4A and MS4A6A were determined in human macrophages. Surface expression of MS4A4A, MS4A6A and TREM2, as well as sTREM2, were measured in macrophages after antibody treatment. Phosphorylation of spleen tyrosine kinase (pSYK) in anti‐MS4A4A pre‐treated macrophages was measured upon triggering of TREM2 signaling with an activating antibody.ResultMS4A4A overexpression in HEK293 cells resulted in an increase in basal calcium influx, but impaired calcium mobilization after depletion of stores. Significant inhibition of TREM2 signaling (pSYK) was observed in HEK293/TREM2+DAP12 cells overexpressing MS4A4A. This effect was partially rescued with a commercial MS4A4A antibody. Similarly, treatment of primary human macrophages with a proprietary anti‐MS4A4A antibody increased pSYK levels after TREM2 activation. Anti‐MS4A4A treatment reduced surface levels of both MS4A4A and MS4A6A, while increasing surface TREM2 and sTREM2. Antibody treatment also led to lipid raft remodeling and cluster formation in macrophages.ConclusionOur findings indicate that, like other MS4A family members, MS4A4A modulates calcium mobilization and receptor signaling. An MS4A4A‐targeting antibody regulates the surface expression of key microglial receptors and induces lipid raft remodeling, which may provide a mechanistic explanation for enhanced TREM2 signaling, ultimately resulting in improved myeloid cell function.
The Biochemical Characterization of LINC00298; a Genetic Risk Factor for the Development of Alzheimer’s Disease
Authors: Whitaker Rachel A Hellmann 
Published: December 2023

AbstractBackgroundLong non‐coding RNAs (lncRNAs) are ubiquitous throughout the human system, yet many of their biological functions remain unknown. LINC00298 RNA, a long intergenic non‐coding RNA (lincRNA), is known to be a genetic risk factor for the development of Alzheimer’s disease, but until now, it had not been biochemically characterized.MethodComputational Modeling was used to develop secondary and tertiary structures of LINC00298 RNA. Liquid Chromatography (LC) and Mass Spectrometry (MS) (LC/MS) was used to identify the protein binding partners of LINC00298 RNA.ResultStructural analysis of LINC00298 RNA indicated it is mostly comprised of stem‐loop secondary structural motifs, with an elongated tertiary structure that is dynamic, making it an ideal binding partner for numerous cellular proteins. Biological analysis of LINC0028 RNA indicated that it has 24 protein binding partners, which include: Histone H1.4, Histone H2AX, Histone H4, Pyruvate kinase, Alpha‐enolase, 40S Ribosomal proteins SA, S18, and S3, 60S Ribosomal proteins L31, L13, L13a, 60S acidic ribosomal protein P0 and P2, Prohibitin 1, ATP Synthase subunit alpha and subunit e, Heat Shock Protein HSP 90‐beta, Heterogeneous Nuclear Ribonucleoprotein A/B, Heterogeneous Nuclear Ribonucleoprotein U, Cofilin‐1 Elongation factor 2, Eukaryotic Initiation Factor 4A‐I, Dihydropyrimidinase‐related protein 2, and ADP/ATP Translocase 2.ConclusionThrough analysis of these 24 protein binding partners, it was concluded that LINC00298 RNA may play significant roles in protein translation, as well as neuronal development, proliferation, and cellular organization. Furthermore, analysis of LINC00298 RNA’s interactome, indicated that LINC00298 RNA has dual localization in the nucleus and the cytosol. This biochemical characterization of LINC00298 RNA highlights the essential role it plays in many biological processes and the important need for continued research on LINC00298 RNA’s pathogenic role in the development of Alzheimer’s disease.
Production pathway of APP669‐x peptides in the cultured cells
Authors: Tomita Taisuke , Yokoyama Miyabishara , Kaneko Naoki , Matsuzaki Masaya , Kobayashi Honoka , Yoshizawa Yota , Naito Hiroki , Sekiya Sadanori , Iwamoto Shinichi , Tanaka Koichi 
Published: December 2023

AbstractBackgroundWe have identified APP669‐711 (a.k.a. Aβ(‐3)‐40) in human plasma using immunoprecipitation combined with matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS), and revealed that the composite biomarker using APP669‐711/Aβ1‐42 ratio correlates with amyloid PET status (Kaneko et al., 2014; Nakamura et al., 2018). We also recently found that A Disintegrin and Metalloproteinase with a Thrombospondin type 1 motif, type 4 (ADAMTS4) is responsible for the APP669‐site cleavage of APP (Matsuzaki et al., Mol Psychiatry 2023). Here, we analyzed the production pathway APP669‐x peptides from the C‐terminal stub c102 of APP, which is c99 with 3 extra N‐terminal amino acid residues (i.e., the cleaved APP fragment at APP669‐site).MethodWe established the endo‐specific antibody against the N terminus of APP669‐x peptide, an anti‐c102 antibody. We analyzed the effect of ADAMTS4 on the production of Aβ‐related peptides from the APP‐expressing HEK293 cells using IP‐MALDI‐MS.ResultWe successfully detected the endogenous C‐terminal fragment of APP specifically reacted with anti‐c102 antibody in A549 cells. We found that the overexpression of the recombinant c102 resulted in the production of a series of APP669‐x peptides by the γ‐secretase. No Aβ starting at the 1st nor 4th position was generated from c102‐expressing cells irrespective of ADAMTS4 expression. Co‐expression of ADAMTS4 with APP increased the production of both APP669‐711 and Aβ4‐40. However, the addition of extracellular ADAMTS4 to HEK293 cells expressing APP resulted in the increase in the Aβ4‐40, but not APP669‐711 nor Aβ1‐40, suggesting that no further N‐terminal trimming of c102 is occurred within the cells after ADAMTS4‐mediated APP669 cleavage.ConclusionThese results indicated that ADAMTS4 cleaves APP in the secretory pathway to generate c102, which is a direct substrate for the γ‐secretase.
Cerebellar atrophy in pathological subtypes of Alzheimer’s disease and related dementias
Authors: Chen Yu , Spina Salvatore , Callahan Patrick , Grinberg Lea T. , Seeley William W. , Kramer Joel H. , Miller Bruce L , Rankin Katherine P 
Published: December 2023

AbstractBackgroundThe cerebellum is differentially affected in various neurodegenerative diseases (Gellersen et al., 2017), but associations of cerebellar atrophy with specific neuropathologies have not been systematically analyzed. We used brain imaging to examine cerebellar grey matter volume with patients with all major pathological subtypes of Alzheimer’s disease and related dementias (ADRD).MethodWe applied voxel‐based morphometry to the earliest structural magnetic resonance imaging scans of autopsy‐proven ADRD cases (n = 309), and age‐, sex‐, and education‐matched healthy controls (n = 80). Seventy‐seven AD cases, 74 cases with mixed Lewy body disease and AD (LBD‐AD), and 158 frontotemporal lobar degeneration (FTLD) cases were included in this study. Patients with FTLD were further classified into FTLD major molecular classes and subtypes: FTLD‐TDP [FTLD‐TDP type A (TDP‐A) (n = 21), FTLD‐TDP type B (TDP‐B) (n = 21), FTLD‐TDP type C (TDP‐C) (n = 26)] and FTLD‐tau [Pick’s disease (n = 25), corticobasal degeneration (CBD) (n = 32), progressive supranuclear palsy (PSP) (n = 33)]. Clinical function was assessed with the Clinical Dementia Rating Scale (CDR) (Morris, 1993; Hughes et al., 1982) at the time of MRI scan, with global score ranging from 0 (normal), 0.5 (very mildly impaired), 1 (mildly impaired), 2 (moderately impaired) to 3 (severely impaired).ResultsCompared with controls, distinct patterns of cerebellar atrophy were observed in all pathological subtypes spanning bilateral hemispheres and vermis (PFWE‐corr<0.05, >100 contiguous voxels). Significant cerebellar grey matter changes were even found in the early stage (CDR ≦ 1) of all subtypes, with the exception of TDP‐B, and in the very early stage (CDR 0‐0.5) of AD, LBD‐AD, TDP‐A and PSP. Degree of cortical atrophy positively predicted degree of cerebellar atrophy in all subtypes.ConclusionThis study is the first to identify distinct early patterns of cerebellar atrophy across pathological subtypes of ADRD, and to show a direct relationship between cerebellar and cortical grey matter volume. These results clarify the cerebellar involvement in ADRD and underscore the potential for cerebellar neuroimaging to be a non‐invasive biomarker for differential diagnosis among pathologies and disease monitoring.
The Effect of Home‐based Cognitive Training Using Workbook and Tablet PC in Presenile Dementia Patients
Authors: Kwon Jay Cheol , Lee Kyungsoo 
Published: December 2023

AbstractBackgroundsAlthough the effectiveness of cognitive training has previously been established, adherence or maintenance to these program is difficult to achieve due to the lack of validated and convenient tools and programs. Furthermore, presenile dementia patients are usually physically no impairment but their welfare systems are overlooked compared to senile patients. The aims of this study are to evaluate the effects of home‐based cognitive training and usefulness of workbook (e.g. regular paper book) and tablet personal computer (e.g. GALAXY pad) focusing on presenile dementia patients.Materials and MethodsWe enrolled 48 dementia patients who met the predefined inclusion criteria from two dementia outpatient clinics. Finally, 34 presenile dementia patients (age; 63.03±4.58, 16 men and 18 women, educational attainment; 10.03±4.30 years, CDR sum of box; 3.21±1.97, MMSE; 21.74±5.24, ADAS‐Cog_total; 20.12±8.13, K‐IADL; 0.43±0.36) were randomly assigned to a 12‐week scheduled cognitive training program using either an workbook (W‐group, age; 62.53±4.03, 9 men and 10 women, educational attainment: 10.05±3.05, CDR_SOB; 3.68±2.07, MMSE; 21.42±5.46, ADAS‐Cog_total 20.95±8.49, K‐IADL; 0.50±0.40) or tablet personal computer (T‐group, age; 63.67±5.26, men 7 and women 8, Education; 10.00±5.63, CDR_SOB; 2.60±1.71, MMSE; 22.13±5.11, ADAS‐Cog_tatal; 19.07±7.81, K‐IADL; 0.33±0.29). All patients underwent 1 hour/day for 5 days/week of training with support with their caregiver. During the program, levels of difficulties were adjusted according to rater’s measurement at regular visits. Before and after the training program, all patients were tested for MMSE, CDR‐SB, IADL and ADAS‐Cog.ResultsOn ADAS‐cog tests, patients showed improvement post training (p = 0.021). T‐group showed more improvement in CDR‐SB than W‐group (P = 0.01). In subgroup analyses including subdomain, there were no significant differences between pre and post tests. All patients and caregivers were well‐tolerated for 12 weeks.ConclusionWe suggest that cognitive training using workbook and tablet personal computer is a well‐tolerated and comparable tool for presenile dementia patients and their caregivers.
Microglial zinc finger protein 335 mediates LPS‐induced neurodegeneration and memory loss as a transcriptional factor for lymphocyte antigen‐6M
Authors: Ni Junjun , Quan Zhenzhen , Qing Hong 
Published: December 2023

AbstractBackgroundZinc finger protein 335 (Zfp335) is a transcription factor that regulates mammalian neurogenesis and neuronal differentiation. It is a causative factor for severe microcephaly, small somatic size, and neonatal death. Here, we evaluated the effects of Zfp335 in the adult mouse brain after lipopolysaccharide (LPS) challenge.MethodWe used wild‐type (WT) and Zfp335 knock‐down (Zfp335+/−) mice with LPS administered in the intracerebral ventricle in vivo and cultured microglia treated with LPS in vitro. The impact of Zfp335 was evaluated by RT‐PCR, RNA‐sequencing, western blotting, immunocytochemistry, ELISA, and the memory behavior tests. Knockdown of Zfp335 expression ameliorated microglia activation significantly, including reduced mRNA and protein expression of Iba1, reduced numbers of microglia, reduced cell diameter, and increased branch length, in the brains of 2‐month‐old mice after LPS treatment.ResultZfp335 was expressed in microglia and neurons, but increased in microglia, not neurons, in the brain of mice after LPS administration. LPS‐induced microglia‐mediated neurodegeneration was dependent upon microglial Zfp335 controlled by nuclear factor‐kappa B. Microglial Zfp335 affected neuronal activity through transcriptional regulation of lymphocyte antigen‐6M (Ly6M).ConclusionOur data suggest that Zfp335 is a key transcription factor that exacerbates microglia‐mediated neurodegeneration through upregulation of Ly6M expression. Inhibition of microglial Zfp335 may be a new strategy for preventing brain disease induced by microglia activation.
Real‐world one‐year estimation of the candidates for lecanemab in a South Korean memory clinic
Authors: Sun Kyunghwa , Lee Sun Min , Park Sun Ah , Moon So Young 
Published: December 2023

AbstractBackgroundResults from an 18‐month Phase 3 clinical trial showed that lecanemab reduced markers of amyloid on early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. As the lecanemab recently received accelerated approval by the US Food and Drug Administation, consideration for prescribing it in the right person, at the right dose and in a very carefully monitored way in a real‐world practice is necessary now.MethodIn this study, we aimed to estimate the candidates for lecanemab in a South Korean memory clinic based on one‐year clinical data. We reviewed retrospectively the medical records of a total 344 patients (211 females, 69.7±9.3 years old) who visited the memory clinic and took the amyloid PET at the department of Neurology, Ajou University Hospital in 2022. We tried to find the patients whose clinical characteristics fit with the inclusion as well as exclusion criteria from the Phase 4 clinical trial of lecanemab.ResultThe patients consisted of 14 subjective cognitive complaints, 139 mild cognitive impairments (MCI), 107 Alzheimer’s disease (AD) dementia, or 84 other neurodegenerative diseases whose amyloid positivity was 28.6%, 43.2%, 72.0%, or 10.7%, respectively. Among patients with evidence of amyloid deposition, 4 MCI and 38 AD dementia were within the exclusion criteria because they scored less than 22 at the Mini‐Mental State Examination (MMSE). Other 7 patients with AD dementia would be also excluded because they scored both Global Clinical Dementia Rating (CDR) score greater than 1 and <22 at the MMSE. One more AD dementia patient had no data of cognitive test. Finally, 56 patients with MCI and 31 patients with AD dementia met the criteria for using the lecanemab.ConclusionOur study showed that amyloid PET was already integrated in the real‐world Korean practice. In addition, the amyloid‐positivity data from real‐world practice in a South Korean memory clinic matched well with previous research data. It is expected that this pattern of the Korean practice might contribute to give real‐world data for prescribing the lecaemab in the future.