bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain connectivity underlying apathy in Alzheimer’s and Parkinson’s diseases
Authors: Gazes Yunglin , Lee Seonjoo , He Ziqian , Huey Edward D. , Heron Campbell J Le , Vanegas Nora 
Published: December 2023

AbstractBackgroundApathy, defined as a lack of motivation towards goal‐directed behavior, is a common neuropsychiatric symptom in Alzheimer’s (AD) and Parkinson’s (PD) disease. However, the mechanism underlying apathy is still unclear. Studies have postulated that the degeneration of frontal cortical and subcortical structures may play a major role in the mechanism of apathy. This study investigates whether associations between degeneration in structural and functional connectivity between frontal and subcortical regions contributes to the development of apathetic behavior and whether these associations differ by diseases.MethodForty‐four patients, 8 with AD, 14 amnestic mild cognitive impairment (aMCI), and 22 PD, received MRI brain scans, a decision‐making behavioral task, cognitive and psychosocial assessments including the dimensional apathy scale (DAS). We quantified functional connectivity and white matter tract integrity for a set of frontal and subcortical regions of interest, and examined the associations among fronto‐subcortical connectivity, behavioral measures, and the DAS. These associations were tested for patient group interactions.ResultCombining AD and aMCI into one patient group, the AD/aMCI group showed worse apathy than PD in terms of the total, the executive, and the behavioral/cognitive subscores (see Table 1), while the DAS emotional subscore was not different between the two groups. For the decision‐making task, the proportion of trial acceptance was similar between the groups, but AD/aMCI had slower decision latency than PD. Group interaction with brain measures was observed in the association between DAS total score and the functional connectivity between the right pars triangularis in the inferior frontal gyrus and the caudate (See Figure 1; interaction effect: beta = ‐.367, p = .0422 FDR corrected). The white matter tract connecting the right pars triangularis to subcortical regions also showed a group interaction with DAS total score but at an uncorrected statistical level (Figure 2; beta = 3.61, p = .0454, uncorrected).ConclusionOur preliminary analyses exposed phenotypic differences in apathy profiles and decision‐making behavior between AD and PD. Furthermore, the observed functional and structural neurodegenerative changes associated with higher apathy severity may also differ between the two diseases. Future analyses in a larger cohort will examine distinct neurodegeneration patterns between the two diseases.
Vascular, Imaging and Cognition Association of China (VICA) Study: Rationale and Design
Authors: Cui Mei , Wang Yingzhe , Jin Zishuo , Wang Mingqi , Dong Qiang 
Published: December 2023

AbstractBackgroundChina has the highest number of patients with dementia in the world, and about 15‐30% of these cases are caused by vascular disease. Currently, the pathophysiological mechanism that cause vascular cognitive impairment (VCI) remain insufficiently understood. Therefore, early diagnosis and prognostic indicators of VCI are critically important for managing its onset and development To this end, several Chinese institutions have joined forces to establish “Vascular, Imaging and Cognition Association of China” (VICA) (Figure 1). The objective of VICA is to identify new targets for intervention and prompting intelligent graded and stratified treatment.MethodVICA is the first large‐scale multi‐center VCI consortium in China. It consists of seven advanced centers and over two hundred primary hospitals across the country. Included VICA are three different populations at risk for VCI: (a) high vascular risk factors for dementia, (b) cerebral small vessel disease, and (c) acute ischemic stroke or transient ischemic attacks (TIA).ResultAll individuals will be enrolled and monitored for at least 1 year using serial neuropsychological assessment, neuroimaging and collection of multi‐omics data from biospecimens (e.g., blood, urine, feces). In addition, a small sample of patients will undergo PET scans to determine whether neurodegenerative pathology (such as amyloid or tau accumulation) contributes to the course of vascular dementia. The enrollment procedure of patients with stroke or TIA is shown in Figure 2.ConclusionThe overall scientific aim of VICA is to guide early clinical diagnosis and early intervention of VCI based on the integration of multiple vascular risk factors, neuroimaging features and biomarkers. VICA represents a unique scientific resource that will help better understand the dynamics of cognitive change in different populations and identify new potential therapeutic targets for this condition.
Aß oligomers peak in early clinical stages of Alzheimer´s disease and proceed Tau pathology
Authors: Blömeke Lara , Rehn Fabian , Kraemer‐Schulien Victoria , Kutzsche Janine , Pils Marlene , Bujnicki Tuyen , Priller Josef , Schneider Anja , Wiltfang Jens , Jessen Frank , Düzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Wagner Michael , Bannach Oliver , Willbold Dieter , Peters Oliver 
Published: December 2023

AbstractBackgroundAß oligomers are synaptotoxic and may initiate neurodegeneration in early stages of Alzheimer´s disease (AD).Method526 patients and controls from the DELCODE cohort were clinically diagnosed and afterwards neurobiologically classified using the ATN‐system. Aß and Tau oligomers were determined using the sFIDA technology.ResultWithin the AD continuum highest oligomer levels in CSF were detected in amyloid positive SCD and MCI. Aß oligomers outnumber in A+T‐ when compared to normal biomarker profile (A‐T‐) or full‐blown AD pathology (A+T+). APOE ε4 was associated with elevated Aß oligomer levels. No differences in Tau oligomers were found.ConclusionThe appearance of Aß oligomers in CSF is an early event within the AD continuum precedeing the maximum of Tau pathology. Targeting Aß oligomers by disease modifying treatment in early disease stages might be crucial and is supposed to have the highest therapeutical potential in AD.
Tau pathway‐based gene analysis in the Alzheimer’s disease continuum identifies CLU and FYN associated with tau deposition on PET in a Korean Cohort
Authors: Yi Dahyun , Nho Kwangsik , Byun Min Soo , Jung Gijung , Ahn Hyejin , Lee Yun‐Sang , Kim Jong‐Won , Park Jong‐Ho , Liu Shiwei , Huang Yen‐Ning , Saykin Andrew J. , Lee Dong Young 
Published: December 2023

AbstractBackgroundAbnormal tau protein aggregation and spreading in the brain is closely linked to cognitive impairment and neurodegeneration in Alzheimer’s disease (AD). The role of genetic variation in brain tau aggregation has not been fully elucidated. Here, we performed pathway‐based candidate gene association analysis to identify novel genes associated with brain tau deposition on PET in a well‐characterized Korean AD continuum Cohort.MethodWe analyzed data for 145 older adults (69 cognitively normal (CN), 38 mild cognitive impairment (MCI), and 38 AD) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of AD (KBASE). We selected 15 candidate genes related to both tau pathways and AD, curated from existing pathway databases, literature mining, and genome‐wide association study findings. We performed gene‐based association analysis of tau deposition measured by 18F‐AV‐1451 PET scans using PLINK. In addition, we performed whole brain voxel‐wise association analysis of identified single nucleotide polymorphisms (SNPs) to investigate their topographic distributions of differences in tau deposition across the whole brain using SPM12. We examined the interaction of the identified SNPs with APOE ε4 carrier status.ResultGene‐based analysis identified CLU and FYN as significantly associated with tau deposition after adjusting for multiple testing. The most significant signals originated from rs149413552 in CLU and rs57650567 in FYN. A voxel‐wise analysis for the two SNPs showed that individuals carrying at least one minor allele demonstrated greater tau throughout the temporal, parietal, and frontal lobes than individuals having no minor alleles (Fig. 1). The two SNPs were associated with greater cortical atrophy of AD‐signature regions and worse global cognition. rs149413552 in CLU was also associated with longitudinal decline in global cognition and immediate verbal memory over two years. APOE ε4 and the two SNPs appeared to exert additive effects on tau levels (Fig. 2). An interaction between rs57650567 in FYN and APOE ε4 carrier status was observed (Fig. 2)Conclusion
CLU and FYN may play a specific role in tau pathophysiology. These risk genes may prove useful for biomarker and therapeutic development. Larger and multiethnic studies are needed to confirm these findings and to determine generalizability across populations.
The effects of a 24‐weeks resistance exercise intervention on global brain amyloid beta levels: Preliminary results of AGUEDA randomized controlled trial
Authors: Solis‐Urra Patricio , Shekari Mahnaz , Olvera‐Rojas Marcos , Fernandez‐Gamez Beatriz , Bellon Dario , Martín‐Fuentes Isabel , Peña Cristian , Gispert Juan Domingo , Erickson Kirk I. , Esteban‐Cornejo Irene 
Published: December 2023

AbstractBackgroundAmyloid‐beta (Aβ) plaques are considered the initiating pathological hallmark of Alzheimer’s disease (AD). While animal studies suggest that physical exercise may have the potential to clear Aβ, there is limited research on humans, particularly in relation to resistance exercise. The aim of this study was to investigate the effect of a 24‐week resistance exercise program on brain Aβ accumulation in cognitively normal older adults.MethodThe study included 79 cognitively normal older adults with valid baseline and follow‐up data who were randomly assigned to either a 24‐weeks resistance exercise program (n = 42) or a wait‐list control group (n = 37) as part of the AGUEDA trial (NCT05186090) (Table 1). Participants underwent T1‐weighted Magnetic resonance imaging and [18F]Florbetaben amyloid‐PET (positron emission tomography) scans at baseline and after a 24‐weeks follow‐up period. Amyloid burden was quantified using the Centiloid (CL) method. Changes in amyloid burden between the groups were analyzed using analysis of covariance on an intention‐to‐treat basis including baseline CL values as covariateResultAt baseline, the CL for the entire sample was 7.27 ± 25.81, and the prevalence of amyloid positivity using a 12 CL cutoff was 21.5% (n = 17, 10 women), with no significant differences between exercise and control group (p = 0.120 and 0.399, respectively). The estimated marginal mean change after 6 months was 3.51 CL for the exercise group and 1.78 CL for the control group, with no significant differences between the groups (CL group difference: 1.73 ± 1.43 SE; z‐score = 0.032), 95% confidence interval (CI): ‐1.13 to 4.59, p = 0.233).ConclusionThe 24‐weeks resistance exercise program did not alter global amyloid brain burden in cognitively normal older adults. Further research with longer exercise interventions and different a manipulation of exercise parameters is needed to elucidate the role of exercise on brain amyloid burden in cognitively normal older adults.
The volume of the accessory‐basal nucleus of the amygdala reduces with tau pathology in AD, but remains normal in non‐AD conditions
Authors: Salman Yasmine , Malotaux Vincent , Colmant Lise , Gérard Thomas , Huyghe Lara , Boyer Emilien , Quenon Lisa , Dricot Laurence , Ivanoiu Adrian , Lhommel Renaud , Kienlen‐Campard Pascal , Hanseeuw Bernard J 
Published: December 2023

AbstractBackgroundIn AD, tau pathology starts in the medial temporal lobe, including the amygdala‐hippocampal complex. The amygdala is composed of subnuclei that until recently could not be distinguished in‐vivo. This has recently been achieved and implemented in FreeSurfer 7. We aimed to investigate the relative atrophy of the amygdala subnuclei in AD and non‐AD disorders, and to evaluate the association with tauopathy.MethodsWe recruited 131 participants who underwent 3D‐T1 brain MRI and 18F‐MK6240 tau‐PET. Amyloid status (A‐/A+) was determined using plasmatic SiMOA assays or cerebrospinal fluid analyses. The participants were classified after neuropsychological evaluation as cognitively normal (CN) individuals (n = 23 A‐CN, n = 23 A+CN), prodromal AD (n = 48 A+MCI), AD dementia (n = 24 A+dementia), or non‐AD disorders (n = 13, A‐MCI/dementia). We tested differences in the global amygdala volume, and amygdala subnuclei volumes according to clinical diagnoses and visual tau‐PET Braak‐stages. We also assessed the relationship between subnuclei volumes, cognition, and tauopathy in the temporal lobe, covarying age, sex, and global amygdala volume.ResultsWe observed that the global amygdala volume was reduced in the A+MCI group compared to CN (A+/A), and further reduced in AD dementia. In contrast, A+CN and A‐CN had similar volumes (Fig.1A). The global amygdala volume was reduced in Braak III‐IV compared to 0‐I‐II. Individuals with Braak V‐VI had similar amygdala volumes than Braak III‐IV (Fig.1B). After adjusting for the global amygdala volume, only the cortical, medial, and accessory‐basal nuclei volumes were significantly reduced in A+MCI (versus A‐CN). Furthermore, the accessory‐basal nucleus volume was reduced in A+MCI/dementia group (n = 72) compared to A‐MCI/dementia (which was not different from CN ((n = 46), Fig.2). Among A+ participants, temporal tau was negatively associated with the volume of the same three nuclei and the central nucleus, even after adjusting for the amygdala volume. These subnuclei volumes were associated with cognitive performance (Fig.3).ConclusionThe atrophy of amygdala, especially the cortical, medial, and accessory‐basal nuclei, is observed in symptomatic AD, and is associated with temporal tau pathology. Whereas the volumes of the global amygdala and most subfields are also reduced in non‐AD disorders, the volume of the accessory‐basal nucleus was reduced only in symptomatic AD patients.
Identification of Distinct and Shared Biomarkers in Cerebral Small Vessel Disease (SVD) through Proteomic Profiling of Cerebrospinal Fluid
Authors: Hristovska Ines , Kumar Atul , Binette Alexa Pichet , van Westen Danielle , Janelidze Shorena , Stomrud Erik , Palmqvist Sebastian , Ossenkoppele Rik , Mattsson‐Carlgren Niklas , Vogel Jacob W , Hansson Oskar 
Published: December 2023

AbstractBackgroundCerebral small vessel disease (SVD) is a cerebrovascular condition associated with age that contributes to dementia, stroke, and other neurological disorders. White matter lesions (WML), microbleeds, and infarcts are hallmarks of SVD, but their molecular mechanisms are poorly understood. The aim of this study was to investigate the CSF proteomic changes underlying the pathogenesis of SVD subtypes.MethodWe analysed CSF samples of controls and SVD patients (295 with WML, 149 with microbleeds and 64 with infarcts, total 894 subjects) from the Swedish BioFINDER‐2 study using the Olink proteomics platform, measuring 1331 proteins. To evaluate differentially expressed proteins, we used generalized linear models, including age, sex and CSF dynamics as covariates. For cell type enrichment analysis, we used scRNA‐seq data (Allen Brain Map) obtained from the middle temporal gyrus.ResultWe identified >400 CSF proteins dysregulated (pFDR<0.05) in subjects with WML and >20 proteins dysregulated in subjects with microbleeds and infarcts compared to controls. Proteins involved in the regulation of the extracellular matrix, including MMP12 (β = 0.2, p<0.0001 for WML; β = 0.07, p = 0.012 for microbleeds; β = 0.078, p = 0.004 for infarcts) and SMOC2 (β = 0.08, p<0.0001 for WML; β = 0.08, p<0.0001 for microbleeds; β = 0.04, p = 0.03 for infarcts), were significantly upregulated in all SVDs. Others were unique to a specific manifestation of SVD, including CHIT1 for microbleeds (β = 0.15, p<0.0001), and S100A4 for WML (β = 0.16, p<0.0001). Upregulated proteins associated with microbleeds were over‐represented in microglial cells (p = 0.037), but proteins associated with WML and infarcts were enriched in vascular leptomeningeal cells (VLMC) (p<0.0001). In addition, the downregulated proteins in WML were significantly enriched in glutamatergic and GABAergic neurons (p<0.0001).ConclusionIn this study, we revealed shared and distinct proteomic signatures of WML, microbleeds, and infarcts. We uncovered distinct cell type signatures among SVDs, which indicated that microglia might be important for the occurrence of microbleeds but vascular leptomeningeal cells for WML and infarcts. In summary, these findings offer new insights into the molecular mechanisms underlying SVDs.
Clinical correlates of Dopamine transporter imaging and EEG biomarkers in Dementia with Lewy bodies
Authors: Baik Kyoungwon , Jeon Seun , Ye Byoung Seok 
Published: December 2023

AbstractBackgroundDiagnostic value of dopamine transporter (DAT) imaging and electroencephalography (EEG) biomarkers in Dementia with Lewy bodies (DLB) is well studied, but their relationships with clinical symptoms in DLB are not elusive. We investigated the association between DAT imaging and EEG biomarkers and clinical characteristics of DLB.MethodWe evaluated the 120 patients with DLB retrospectively. Quantitative analysis of DAT imaging was performed and uptakes for caudate, putamen, and ventral striatum (VST) were assessed. Frequency of posterior dominant rhythm and theta/beta ratio (TBR) were used as EEG biomarkers. Four core clinical features of DLB were assessed. Firstly, correlation analysis between biomarkers and clinical symptoms were assessed. Regression analyses with significantly correlated biomarkers as model variable were performed to investigate the association between clinical characteristics and biomarkers. Age, sex, and education were used as covariates.ResultParietal TBR (B = 0.498, P = 0.023) and putaminal DAT uptake (B = ‐0.609, P = 0.010) were related to the presence of fluctuation. The severity of visual hallucination was associated with the higher parietal TBR (B = 0.391, P = 0.045) and lower DAT uptake in putamen (B = ‐0.520, P = 0.010) and. Putaminal DAT uptake was related to the presence of REM sleep behavior disorder (B = ‐0.646, P = 0.010). Severity of parkinsonism was associated with the frontal TBR (B = 3.353, P < 0.001).ConclusionDAT imaging and EEG biomarkers were related to the clinical symptoms in DLB differently. In addition, TBR reflects characteristics of DLB better than posterior slow activity.
Eligibility in the INTERCEPT‐AD trial: visual amyloid classification for equivocal SUVrs in early Alzheimer’s disease
Authors: Poppe Tanya , Feaster Todd , Manber Richard , Skljarevski Vladimir , Fuin Niccolo , Siemers Eric R 
Published: December 2023

AbstractBackgroundPET tracers enable the in‐vivo measurement of amyloid in the brain and have been incorporated in eligibility criteria for clinical trials. Automated quantitative image analysis enables the calculation of a standardised uptake value ratio (SUVr) which can enable a rapid amyloid classification without requiring a visual read. However, quantitative analysis may have an equivocal range where amyloid classification does require a visual read. The range of SUVrs that is equivocal is not well understood.MethodParticipants in the INTERCEPT‐AD trial of ACU193 (Siemers et al., J Prev Alzheimers Dis. 2023;10(1):19‐24) underwent an amyloid [18F] Florbetapir PET scan and T1‐weighted MRI scans. MRIs were segmented using the LEAP algorithm (Wolz et al., NeuroImage. 2010;49(2):1316‐1325), registered to the PET image, and the global cortical average (GCA) SUVr based on brain regions typically with high amyloid load in Alzheimer’s disease (Klunk et al., Alzheimers Dement. 2015;11(1):1‐15) was calculated, using the whole cerebellum as the reference region. SUVrs greater than 1.2 were classified as amyloid positive, SUVrs less than 1.0 were classified as amyloid negative, and SUVrs in the equivocal range were assessed by visual read by trained central radiologists.ResultsOf 194 participants who underwent screening, 188 had an SUVr available from automated analysis. Of these, 64 were within the equivocal range (SUVr 1.0 – 1.2) and had a visual read performed. For PET scans in the equivocal range, 53 (83%) were classified as amyloid negative and 11 (17%) were classified as amyloid positive by visual read. Within the equivocal range, there was no difference in SUVrs between the images classified by visual read as amyloid negative or positive.ConclusionSUVrs may be used as an objective quantitative amyloid classification method at values > 1.2 for trial inclusion; however, in the equivocal range, the GCA SUVr did not correspond with amyloid classification based on a visual read. Further study is required to investigate the equivocal range and the use of combined quantitative measures and visual reads.
The Potential of Dendrimers as Alzheimer’s Disease Nanotherapeutics – Evidence of Antiamyloidogenic Properties Against Aβ42
Authors: Moreira Débora A. , Santos Sofia D. , Leiro Victoria , Pêgo Ana P. 
Published: December 2023

AbstractBackgroundToday, available therapies for Alzheimer’s disease (AD) fail to modify the disease progression for the major AD clinical stages [1]. Therefore, new therapeutic approaches are an urgent need. Within nanomedicine, the use of nanomaterials, and dendrimers in particular, pose as promising AD therapies [2]. Dendrimers are globular macromolecules, with a well‐defined and hyperbranched structure, controllable nanosize (<15 nm) and multivalent surface. Due to their intrinsic characteristics, they are first‐in‐class for drug delivery as they can act as efficient and multivalent carriers of different therapeutic molecules. In addition, dendrimers can be used as a drug per se. Different types of dendrimers display antioxidant, anti‐inflammatory, anti‐prion and anti‐amyloidogenic properties [2]. With that in mind, a proprietary family of dendrimers was explored to hamper Aβ (1‐42) peptide aggregation.MethodThe dendrimer was synthesized following a divergent strategy up to generation 3 and characterized by nuclear magnetic resonance and Fourier‐transform infrared spectroscopy. To analyse the dendrimer’s effect on fibrillation, the aggregation kinetics of the Aβ (1‐42) peptide was studied by thioflavin T (ThT) in the presence of different dendrimer concentrations. The aggregates’ morphology was assessed by transmission electron microscopy. The cytotoxicity of dendrimers was evaluated in SH‐SY5Y cells by metabolic assays (resazurin).ResultThe dendrimers showed to interfere with Aβ fibrillation in a concentration‐dependent manner. Their behaviour was similar to fibrillation inhibitors that can break fibrils as well [3]. When at a lower molar ratio than Aβ, dendrimers hampered fibrillation and small/nonfibrillar aggregates were present. For a higher molar ratio (dendrimer/peptide ratio >1), they promoted Aβ fibrillation as more fibrils were present. More importantly, they were shown non‐toxic for neuroblastoma cells.ConclusionIn conclusion, these results show that these dendrimers can interfere with Aβ fibrillation. Future studies will be performed to understand the mechanism of action of this new family of dendrimers.