bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amyloid pathology is associated with semantic loss in patients with subjective cognitive decline
Authors: van den Berg Rosanne L. , de Boer Casper , Zwan Marissa D. , van Harten Argonde C. , Dubbelman Mark A. , Mank Arenda , Kroeze Lior A. , Verberk Inge M.W. , van Berckel Bart N.M. , Teunissen Charlotte E. , van der Flier Wiesje M. , Sikkes Sietske A.M. 
Published: June 2023

AbstractBackgroundEvidence is emerging that subtle language decline is an early indicator of Alzheimer’s disease (AD). This study assessed change in semantic and letter fluency in individuals with subjective cognitive decline (SCD), and examined whether trajectories differed between individuals with and without amyloid‐beta (Aβ)‐pathology.MethodLongitudinal data from 437 individuals of the memory clinic‐based Amsterdam Dementia Cohort were included (Age 61±8 years, 184(42%) Female, follow‐up time 5.3±3.7 years; Table 1). Participants were classified as SCD at baseline, had available baseline Aβ‐information and had at least 1 follow‐up on semantic or letter fluency. Baseline Aβ‐status was dichotomized as positive/negative based on local cut‐offs for Aβ1‐42 concentrations in cerebrospinal fluid, or visual inspection of amyloid positron emission tomography‐imaging (Florbetapir or PiB). Two linear mixed models (LMM) were used to investigate change on semantic and letter fluency. Models included time and time*Aβ‐status as predictors of interest, a random intercept for participant, and age, sex, education were adjusted for. LMMs were subsequently stratified for Aβ‐status.ResultAt baseline, the groups did not differ in semantic (p = 0.313) or letter fluency (p = 0.294). Over time Aβ‐positive individuals changed more rapidly on semantic fluency compared to Aβ‐negative individuals (β = ‐0.32,CI = ‐0.49 – ‐0.14;p<.001). The Aβ‐positive group declined with 0.35 words per year (CI = ‐0.49 – ‐0.20;p<.001), while Aβ‐negative individuals did not show change (β = 0.03;CI = ‐0.12 – 0.06;p = 0.496) (Figure 1). On letter fluency Aβ‐positive individuals changed differently compared to Aβ‐negative individuals (β = ‐0.38;CI = ‐0.72 – ‐0.04;p = 0.028), to the extent that the Aβ‐positive group did not progress (β = 0.10;CI = ‐0.21 – 0.41;p = 0.533), while Aβ‐negative individuals improved with 0.47 words per year (CI = 0.29 – 0.65;p<.001) (Figure 2).ConclusionOur results indicate that Aβ‐positive individuals decreased on semantic fluency, but remained stable on letter fluency. In contrast, Aβ‐negative individuals remained stable on semantic fluency, while they improved on letter fluency over time, which might suggest a learning effect. These findings suggest that the presence of Aβ‐pathology is characterized by semantic loss, highlighting the potential of language based performance as a biomarker for Aβ‐pathology in SCD.
Brain free‐water increases in mild behavioral impairment
Authors: Ji Fang , Kan Cheuk Ni , Lau Jia Ming , Chong Eddie , Xu Xin , Tan Boon Yeow , Venketasubramanian Narayanaswamy , Pasternak Ofer , Chen Christopher Li‐Hsian , Zhou Juan Helen 
Published: June 2023

AbstractBackgroundMild behavioural impairment (MBI) is proposed as a diagnostic construct to identify dementia‐free individuals with sustained neuropsychiatric symptoms as an early manifestation of dementia. Our previous study has demonstrated that MBI predicts faster cognitive decline and progression to dementia. Other studies have shown that MBI was associated with Alzheimer’s disease biomarkers for Aβ and tau. However, cerebrovascular disease (CeVD), which is another critical pathology in dementia, has not been investigated in MBI. Here, we sought to test brain free‐water (FW) alterations, a marker for CeVD, in MBI compared with non‐MBI participants and their associations with longitudinal changes in cognition, function, and neuropsychiatric symptoms.MethodLongitudinal global cognitive scores, clinical dementia rating sum‐of‐boxes (CDR‐SoB), neuropsychiatric inventory (NPI) scores, over 5 years were reported in 281 dementia‐free participants (40 MBI and 241 non‐MBI). MBI was diagnosed using established criteria. All participants underwent T1‐weighted structural and diffusion MRI at baseline. FW imaging method was applied to derive individual‐level white matter (WM) and grey matter (GM) FW maps from diffusion MRI. We compared baseline GM‐FW and WM‐FW between non‐MBI and MBI subjects. We then tested the associations of MBI‐related FW increase with baseline and longitudinal changes in global cognition, CDR‐SB, and NPI scores using linear regression models.ResultMBI had greater GM‐FW in executive control (prefrontal), motor sensory (precentral), attention (insula) and memory (left temporal and right cingulate and cuneus) networks and widespread higher WM‐FW compared with non‐MBI (Fig‐1). Both higher GM‐FW and WM‐FW were associated with lower global cognition, higher CDR‐SB, and higher NPI scores across all participants at baseline (Table‐1). There was no interaction effect of MBI status on such association. Moreover, higher baseline GM‐FW and WM‐FW were associated with longitudinal worsening in global cognition, CDR‐SB, and NPI scores (Table‐2). Interestingly, such associations were greater in MBI than in non‐MBI (Fig‐2).ConclusionThis study demonstrated that MBI was associated with increased brain FW, which may have contributed to the relationship between persistent neuropsychiatric disturbances and clinical and cognitive outcomes. Early detection of cerebrovascular‐related FW alteration may allow for timely management of MBI individuals before development of dementia.
Stages of retinal tauopathy and its relation to age and non‐AD retinal pathologies
Authors: Thal Dietmar Rudolf , Ronisz Alicja , Van Ginderdeuren Rita , Lemmens Sophie , Stalmans Ingeborg , De Groef Lies , Walkiewicz Grzegorz 
Published: June 2023

AbstractBackgroundRetinal imaging for Alzheimer’s disease (AD) pathological features is a potential biomarker for AD. Amyloid β‐protein (Aβ) containing plaques and abnormally phosphorylated tau (p‐tau) pathology have been reported in retinas of AD cases. However, little is known about these pathologies in the retinas of patients without clinically known AD. Therefore, we analyzed retina samples from autopsy and biopsy cases from individuals without known AD for Aβ and tau pathology, to clarify the role of these lesions in non‐AD individuals with and without other eye disorders.MethodWe analyzed retina samples from 140 biopsy and 3 autopsy cases (age: 34 – 96 years; mean: 67 years). Paraffin‐embedded cross‐sections of the retina were stained with hematoxylin & eosin and with antibodies against Aβ and different p‐tau species. Additionally, we screened for the presence of fibrillar tau aggregates with the Gallyas silver method.ResultAβ plaques were not detected. We found a hierarchical sequence of the expansion of p‐tau pathology in the retina, which allowed to distinguish four stages of retinal tauopathy distribution: 0 = no retinal tauopathy (n = 36); 1 = pS202/pT205‐tau pathology restricted to the outer plexiform layer (OPL) (n = 41); 2 = pS202/pT205‐tau pathology restricted to OPL and inner nuclear layer (INL) (n = 23); stage 3 = pS202/pT205‐tau pathology in OPL, INL, and inner plexiform layer (n = 43). Antibodies against pS202/pT205‐tau, pT231‐tau, and MC1‐tau showed comparable results. Neurofibrillary tangles were not found. The distribution of the stages was not associated with age. However, all three non‐diseased controls did not exhibit retinal tauopathy whereas more than 70% of the cases with ocular tumors, inflammation, retina degeneration, and/or gliosis showed signs of a retinal tauopathy.ConclusionHere, we describe the presence of a retinal tauopathy in individuals over 33 years of age. It shows three stages in its evolution, which were in our sample not associated with age but with the occurrence of significant ophthalmopathological alterations. Whether these changes represent a primary retinal tauopathy or an initial stage of retinal AD pathology requires future studies.FundingStichting Alzheimer Onderzoek SAO‐FRA 2020‐017
Different cutoffs definitions to evaluate the concordance between CSF Ab42 and Ab42/Ab40 across neurodegenerative diseases
Authors: Delaby Constance , Estellés Teresa , Zhu Nuole , Arranz Javier , Barroeta Isabel , Carmona‐Iragui Maria , Illán‐Gala Ignacio , Santos‐Santos Miguel A , Altuna Miren , Sala Isabel , Sánchez‐Saudinós Mª Belen , Videla Laura , Valldeneu Sílvia , Subirana Andrea , Tondo Mireia , Blanco‐Vaca Francisco , Lehmann Sylvain , Belbin Olivia , Blesa Rafael , Fortea Juan , Lleó Alberto , Alcolea Daniel 
Published: June 2023

AbstractBackgroundCerebrospinal fluid (CSF) Aβ1‐42 and the Aβ1‐42/Aβ1‐40 ratio are markers of amyloid pathology. We aimed to compare their agreement in different neurodegenerative disorders applying different cutoffs.MethodWe included 1564 participants from the Sant Pau Initiative on Neurodegeneration (SPIN), with AD, dementia with Lewy bodies (DLB), frontotemporal lobar degeneration‐related syndromes (FTLD), cognitively impaired but non‐neurodegenerative conditions (others), and cognitively normal individuals (CN). Cutoffs were defined as one‐sided 97.5%, 95% and 90% (Q97.5%, Q95% and Q90%, respectively) quantiles values in a middle‐aged cognitively normal population. These cutoffs for Aβ1‐42 (617 pg/mL, 637 pg/mL and 732 pg/mL, respectively) and Aβ1‐42/Aβ1‐40 (0.060, 0.070 and 0.082, respectively) were used to classify all participants as “positive” or “negative” according to each marker. We compared concordance of Aβ1‐42 and the Aβ1‐42/Aβ1‐40 ratio between groups through X2 test and correlations with Spearman test.ResultCorrelation between Aβ1‐42 and the Aβ1‐42/Aβ1‐40 ratio in CSF was strong (0.71, p<0.001) in the whole cohort, DLB and others groups (0.69 and 0.64, respectively, both p<0.0001); correlation was weak in AD, FTLD and CN groups (0.33, 0.52 and 0.51, respectively, all p<0.0001). Using Q97.5%, Q95% and Q90% cutoffs, Aβ1‐42 and ratio had an overall agreement of 76.6%, 78.3% and 82.9%, respectively in the whole sample. Both measures were normal (« negative ») in 46.1%, 41.6% and 35.8%, and both were abnormal (« positive ») in 30.5%, 36.7% and 47.1% of participants, respectively. Within each diagnostic category, the agreement ranged from 64% (AD) to 91.5% (CN) using Q97.5%, from 69.6% (AD) to 88.7% (CN) using Q95% and from 78.9% (DLB) to 85.9% (AD) using Q90%. Regardless of the cutoff definition, most discordant cases in AD and DLB were due to normal Aβ1‐42 and low ratio, while discordant cases in FTLD were more frequently due to low Aβ1‐42 and normal ratio.ConclusionAlthough Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio may reflect the same pathophysiological pathway, their agreement depends on cutoff definition. Our results confirm that both parameters show medium to high concordance, and that in case of discordance, Aβ1‐42 positivity with negative ratio is more associated to non‐AD dementias, independently of the cutoff used.
The predictive turn in Alzheimer’s disease (PreTAD)
Authors: Snijders Katharina Elisabeth , Stümpel Johanne , Rostamzadeh Ayda , Ribaldi Federica , Marquié Marta , Schmitz‐Luhn Björn , Boada Mercè , Frisoni Giovanni B , Jessen Frank , Woopen Christiane , Schwegler Carolin 
Published: June 2023

AbstractBackgroundDiagnostics for early detection and risk prediction in Alzheimer’s disease (AD) are constantly evolving. Blood‐based biomarkers may replace more invasive and expensive methods (such as CSF and PET) and lead to a higher accessibility in the detection of AD pathology. These developments may result in an extended availability of risk prediction, also for patients with subjective cognitive decline (SCD) or symptom‐free individuals at risk. The PreTAD project aims at providing data and analyses on people’s perspectives towards prediction as well as the effect of predictive medicine on individuals and society from a clinical, ethical, legal and linguistic point of view.MethodThe empirical survey of PreTAD will focus on three different groups: 150 healthy participants with a family history of AD or APOE4 carriership; 150 participants with previously diagnosed SCD and 90 participants with newly diagnosed SCD ≤ 4 weeks. The participants will be studied with standardized quantitative tests, including newly developed assessments and will be provided with hypothetical scenarios of AD‐biomarker risk outcomes and disclosure. The longitudinal survey will be conducted by specialized Memory Clinics in Cologne, Geneva and Barcelona over a period of 6 months. To achieve a comprehensive approach, the trial design of our interdisciplinary collaboration combines quantitative assessment with qualitative (narrative) interviews, as well as ethical and legal analyses. In this presentation, we report the design of the study.ResultOur study serves to understand the perspectives, needs and preferences of cognitively healthy individuals with increased risk for AD regarding early AD‐biomarker testing and risk prediction of dementia. We will also obtain information on the participants understanding of risk and expectations towards risk prediction. It will also focus on psychological distress during the process of risk prediction, subjective well‐being, quality of life, identity and self‐perception measures as well as the willingness to undertake lifestyle changes and prevention.ConclusionOur trinational project aims to contribute to the urgent need of creating a framework for good clinical practice regarding the prediction of AD in presymptomatic at‐risk‐stages.
Evaluating Dementia Neuroanatomic Risk of a Clinical Cohort Using MRI
Authors: Casanova Ramon , Barnard Ryan , Hsu Fang‐Chi , Lockhart Samuel N. , Bateman James R. , Rundle Melissa M. , Gaussoin Sarah A. , Hughes Tim M. , Whitlow Christopher T. , Sai Kiran K Solingapuram , Hayden Kathleen M. , Espeland Mark A. , Craft Suzanne 
Published: June 2023

AbstractBackgroundMRI is a widely used modality to evaluate dementia risk. Here, we extend previous work by estimating the Alzheimer’s disease pattern similarity (AD‐PS) scores for participants of a community‐dwelling older adult cohort to evaluate neuroanatomic risk of AD using MRI.MethodBaseline MRI data were available from 522 participants from the Wake Forest Alzheimer’s Disease Research Center’s (ADRC) Clinical Core with mean age 70.2, 81.2% White and 17.6% African American. Of those, 253 were cognitively impaired (dementia and mild cognitive impairment (MCI)) and 138 underwent [11C]PiB PET (MCI = 48 and dementia = 19). Global PiB SUVR was averaged from a cortical region of interest sensitive to early AD. Participants were classified as amyloid positivity using a previously defined threshold (≥1.21 SUVR). AD‐PS scores were estimated based on GM probability maps according to previously reported machine learning methodology[1]. High‐dimensional classifiers were trained using ADNI MRI data. To generate the AD‐PS scores, MRI data from the ADRC cohort was provided as input to the classifiers.We investigated associations that AD‐PS scores [range 0‐1] had with amyloid positivity and cognitive impairment. All analyses were adjusted for age, sex, race and education. AD‐PS scores discrimination of participants with dementia versus normal cognition (CN) was compared to hippocampal volume and cortical thickness in temporal regions based meta‐ROI which are sensitive to AD.ResultAD‐PS scores were strongly associated with cognitive impairment: OR = 4.1, CI: 95% [2.9‐5.9], p<0.0001. In addition, they were associated with amyloid positivity with OR = 2.8,CI: 95% [1.7‐4.7], p<0.001, N = 138. These amyloid positivity results did not hold in analyses limited to CN participants only(N = 71). Performance when discriminating patients with dementia from CN individuals was highest for AD‐PS score (AUC = 92.2, CI: 95% [86.9‐97.5]), followed by hippocampal volume (AUC = 86.5, CI: 95% [81.1‐91.2]) and cortical thickness in temporal regions based meta‐ROI (AUC = 81.5 CI: 95% [74.4‐88.6], See‐Figure).ConclusionThis work highlights further the generalization performance of our machine learning algorithm. AD‐PS scores, a measure of dementia neuroanatomic risk, strongly discriminated individuals with dementia from CN individuals in the Wake Forest ADRC.
References
[1] Casanova et. al., Alzheimer’s & Dementia, 2021, PMID:34310039.
Region specific reduction of neurogranin immunostaining in the hippocampus of Alzheimer’s disease brains
Authors: Vontell Regina T , Davis David A. , Dallmeier Julian , Barreda Ayled , Blennow Kaj , Zetterberg Henrik , Kvartsberg Hlin , Gultekin Sakir Humayun , DeKosky Steven T , Rundek Tatjana , Scott William K. , Sun Xiaoyan 
Published: June 2023

AbstractBackgroundNeurogranin (Ng) is a post‐synaptic protein involved in formation of long‐term potentials, and thus plays an important role in learning and memory. The concentration of Ng is increased in the cerebrospinal fluid (CSF) of people with Alzheimer’s disease (AD), and CSF Ng is considered to be a biomarker for synaptic dysfunction in AD. The expression of Ng protein in the human brain and its association with AD pathology, however, are less well studied.MethodUsing immunohistochemical detection methods we investigated the protein expression of Ng, beta‐amyloid (Aβ) and hyperphosphorylated paired helical filament tau (phospho‐tau; ptau) in the post‐mortem hippocampus from 12 AD patients and 12 cognitively unaffected controls (NC). We compared the number of positively stained cells (Ng, ptau) or plaques (Aβ) in the hippocampal sub‐regions (dentate gyrus, Cornu Ammonis (CA) fields 1‐3) from the 2 groups. Donor samples with intermediate AD (i.e., Braak stage III‐IV) or NC (Braak 0‐I/II) were analyzed using Image Pro Premier automated image analysis software (version 10.01). The data were normalized to the number of cells or clusters/mm2 and analyzed using a one‐way ANOVA. Using a test of circularity (Cir = (4*A)/Pi*MaxFeret2), we further investigated morphological differences in the Ng positive neurons by measuring the Ng expression in the apical dendrite of pyramidal neurons.ResultThere was a 40% reduction of Ng immunopositive neurons in AD compared to NC in the CA3(N = 24;p = 0.0003) and in the CA1(N = 24;p = 0.014) hippocampal sub‐regions. Ng positive cells did not change significantly in AD compared to NC in the other hippocampal regions. Additionally, we showed that CA1 region, Ng was localized mainly in the neuronal cell soma of AD donors, while its expression extended into the apical dendrites of NC donors (N = 24;p = 0.006). In AD, Ng immunostaining negatively correlated with ptau immunopositive neurofibrillary tangles (r = ‐0.70;p = 0.04)ConclusionSelective loss of Ng immunostaining in certain subregions of the hippocampus suggests that synaptic damage in AD maybe a region‐specific event. The mechanism underlying such regional synaptic damage and the changes in Ng expression will be key in understanding the selective vulnerability of brain regions to AD.
Investigating the effects of centella asiatica on neuroinflammation in beta‐amyloid overexpressing mice
Authors: Speers Alex B , Brandes Mikah S , Kedjejian Nareg E , Matthews Donald G , Caruso Maya , Wright Kirsten M , Quinn Joseph F , Soumyanath Amala , Gray Nora E 
Published: June 2023

AbstractBackgroundCentella asiatica is a medicinal plant traditionally used for promoting brain health and improving cognition. Our lab has shown that a water extract of Centella asiatica (CAW), can enhance mitochondrial function, promote antioxidant response, and improve cognitive deficits in mouse models of aging and Alzheimer’s disease (AD). Because neuroinflammation is also prevalent in the AD brain and there is growing evidence that the interplay between oxidative stress, mitochondrial dysfunction, and neuroinflammation play a central role in the progression of AD, here we explore the effects of oral CAW treatment on neuroinflammation in the 5xFAD mouse model of beta‐amyloid accumulation.MethodsEight to nine month old male and female 5xFAD mice were treated with 0 or 1000 mg/kg/day of CAW administered in their drinking water or integrated into their diet (AIN‐93M rodent diet) for a total of 5 weeks, after which brain samples were collected. Microglial and astrocytic activation as well as beta‐amyloid pathology is currently being assessed by immunohistochemistry (IHC). Expression of pro‐ and anti‐inflammatory cytokines is also being determined by qPCR in brain samples from these treated animals.ResultsPreliminary IHC results suggest that CAW administered in the diet reduces the heightened microglial activation found in 5xFAD mice. Our ongoing analysis will determine if there are also effects on astrocytic activation and beta‐amyloid pathology, and whether these effects vary if the CAW is administered in the drinking water rather than the diet. Additionally, gene expression assessments are currently underway on these samples to evaluate the effects of CAW on the expression of pro‐ and anti‐inflammatory cytokines.ConclusionInitial data suggests an anti‐inflammatory effect of the CAW extract. Results will continue to be collected over the next few months, further clarifying our preliminary results as well as generating data for the potential mechanisms or cell types that may mediate the effect of CAW on neuroinflammation. Moreover, we will learn whether the mode of administration, in the diet versus the drinking water, has an effect on the response to CAW, which would have important implications for future experimental design as well as the development of CAW for clinical use.
An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE‐ε4 in Alzheimer’s disease
Authors: JIANG Yuanbing , Zhou Xiaopu , Wong Hiu Yi , Li Ouyang , Ip Fanny C. F. , Chau Vicky M.N. , Lau Shun‐Fat , Wu Wei , Wong Daniel Y.K. , Seo Heukjin , Fu Wing‐Yu , Lai Nicole Chit Hang , Chen Yuewen , Chen Yu , Tong Estella Pui‐Sze , Mok Vincent C.T. , Kwok Timothy CY , Mok Kin Y , Shoai Maryam , Lehallier Benoit , Moran‐Losada Patricia , O’Brien Eleanor , Porter Tenielle , Laws Simon M , Hardy John A. , Wyss‐Coray Tony , Masters Colin L. , Fu Amy K.Y. , Ip Nancy Y. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: June 2023

AbstractBackgroundGenetic factors are increasingly being recognized as important contributors to the pathogenesis of Alzheimer’s disease (AD). While the expression of most AD risk genes is enriched in microglia, which leads to microglial dysfunction and amyloid‐beta (Aβ) accumulation, emerging studies suggest that changes in the brain micro‐environment—typically changes in the levels of soluble factors—also modulate microglial functions and disease‐related pathological changes. Therefore, understanding the genetic regulation and pathogenic roles of those soluble factors in AD will help clarify the pathophysiological mechanisms of the disease.MethodWe examined the changes in the level of soluble ST2 (sST2), a decoy receptor of IL‐33/ST2 signaling, in the blood and brains of patients with AD, and performed a genome‐wide association study (GWAS) for sST2 to understand its genetic regulations.ResultWe showed that elevated sST2 levels are associated with more severe neurodegeneration and Aβ pathological lesions in patients with AD. Our GWAS analysis identified a genetic variant in IL1RL1 (the gene encoding sST2) that is associated with decreased sST2 levels in the blood and brain in AD. Furthermore, we demonstrated that female APOE‐ε4 carriers harboring the genetic variant exhibit decreased sST2 level and reduced risk of AD as well as decreased Aβ accumulation through enhancing microglial activation and colocalization with Aβ.ConclusionThese findings demonstrate how sST2 level in the brain milieu is modulated by a genetic variation and plays a disease‐causing role in AD through microglial clearance of Aβ, and might thus be a novel target for AD therapy.