bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three‐Objects‐Three‐Places Test: Association with Alzheimer’s Disease Biomarkers
Authors: Krug Sophie , Ribaldi Federica , Altomare Daniele , Garibotto Valentina , Tomczyk Szymon , Scheffler Max , Lovblad Karl‐Olof , Fernandez Aldara Vazquez , Chicherio Christian , Frisoni Giovanni B 
Published: December 2022

AbstractBackgroundThe Three‐Objects‐Three‐Places Psychological Test (3O3P) assesses episodic memory and has been developed to screen for Alzheimer’s Disease (AD). To perform the test, the clinician shows the patient three objects and hides them in three separate locations. The patient is later asked what the objects and hiding places were, and which object was hidden where, producing a score out of 9. The aim of this study was to investigate if 3O3P scores were associated with common AD biomarkers to test its potential efficacy in detection of AD pathology, and how these associations compared with other common AD neuropsychological tests.Method166 patients from the Geneva Memory Centre cohort (106 MCI, 19 dementia, and 41 unimpaired) who underwent amyloid‐PET, tau‐PET, MRI, as well as clinical and neuropsychological assessments, were included. The biomarkers tested included amyloid (A) and tau (T) load, and cortical thickness (N). Associations between these biomarkers and 3O3P scores, MMSE and delayed total recall scores (DTR; extracted from the 16‐item Free and Cued Recall) were tested. The associations between biomarkers and test scores were investigated using linear regression.ResultMean patient age was 71 years, 52% were female, and mean years of education was 14. When controlling for age and education, 3O3P scores were negatively associated with amyloid (b = ‐0.02, p<0.001), tau load (b = ‐4.14, p<0.001), and positively with cortical thickness (b = 7.21, p<0.001). Similar trends were seen between these biomarkers and MMSE (A: b = ‐0.02; T: b = ‐5.21; N: b = 8.18, p<0.001) and DTR scores (A: b = ‐0.03; T: b = ‐5.28; N: b = 10.2, p<0.001).ConclusionThese preliminary findings indicate that 3O3P scores correlate significantly with the AD biomarkers tested, as do MMSE and DTR scores. However, the 3O3P test carries advantages, such as its short duration, easy administration, and not requiring the examiner to purchase equipment or score sheets. Further analysis is needed to clarify the relationship between 3O3P scores and AD biomarkers.
Modifying effect of AD pathology in the association between CSF synaptic biomarkers and brain function and structure in preclinical Alzheimer
Authors: Milà‐Alomà Marta , Cacciaglia Raffaele , Shekari Mahnaz , Operto Grégory , Brinkmalm Ann , Kvartsberg Hlin , Ashton Nicholas J. , Kollmorgen Gwendlyn , Wild Norbert , Suridjan Ivonne , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis , Gispert Juan Domingo , Suárez‐Calvet Marc 
Published: December 2022

AbstractBackgroundPrevious studies have shown that synaptic biomarkers are increased in CSF in the preclinical stage of Alzheimer’s disease (AD). However, little is known about how CSF synaptic biomarkers associate with structural and functional brain measures in preclinical Alzheimer. The aim of this study was to test the association of CSF synaptic biomarkers with brain metabolism and structure in preclinical Alzheimer and explore whether these associations were modified by AD pathology.MethodWe studied 328 cognitively‐unimpaired individuals of the ALFA+ cohort. Participants underwent lumbar puncture, [18F]‐FDG PET scan and structural MRI. The following synaptic biomarkers were measured in CSF: neurogranin (NeuroToolKit [a panel of automated robust prototype immunoassays], Roche Diagnostics International Ltd), GAP‐43 (ELISA), SNAP‐25 and synaptotagmin‐1 (IP‐MS). We performed voxel‐wise analyses to test the association of each synaptic biomarker with brain metabolism and grey matter volume, using a threshold of p<0.005 and a minimum cluster size of 100 voxels. Participants were categorized by AT groups (A+ if CSF Aβ42/40<0.071 and T+ if CSF p‐tau>24pg/ml) and interaction terms with each synaptic biomarker were evaluated.Result212 (64.6%) participants were A‐T‐, 91 (27.7%) were A+T‐ and 25 (7.6%) were A+T+. To focus the study on the AD continuum, A‐T+ participants (n=12) were excluded. When assessing all participants, positive associations between each CSF synaptic biomarkers and FDG PET uptake and grey matter volume were found in brain areas including the caudate, the insula, cingulate gyrus and inferior temporal and parietal gyrus (Fig 1A). AT status modified the associations with both FDG PET uptake and grey matter volume. Compared to A‐T‐, A+T+ participants showed a positive association of CSF neurogranin, GAP‐43 and synaptotagmin‐1 with FDG PET uptake in the precuneus. Conversely, CSF synaptic biomarkers were negatively associated with grey matter volume with progressive AD pathology (A‐T‐>A+T‐>A+T+) in several brain regions including the cingulate gyrus and middle and superior frontal gyrus (Fig 1B).ConclusionIn preclinical Alzheimer, CSF synaptic biomarkers show associations with functional and structural brain measures, which are modified by AD pathology. Progressive AD pathology is associated with increased brain metabolism and decreased grey matter volume in several AD‐related brain regions.
Measurement equivalence of the NACC UDS neuropsychological battery across race/ethnic groups
Authors: Gaynor Leslie S , Lopez Francesca , Van Hulle Carol A. , Li Clara , Vasunilashorn Sarinnapha M , Simone Stephanie M. , Mungas Dan M. 
Published: December 2022

AbstractBackgroundThe National Alzheimer’s Coordinating Center (NACC) maintains a national database of clinical and cognitive data collected under a standard protocol set by the National Institute on Aging (NIA) called the Uniform Data Set (UDS). Development of factor scores unbiased by race/ethnicity will allow for comparison of other lifestyle and psychosocial factors within the NIA health disparities framework. The present study examined the dimensional structure of the comprehensive neuropsychological test battery and factorial equivalence across racial/ethnic groups.Method43,999 participants (Table 1; Age: Mean = 71.6, Education: Mean = 15.8; Latinx: N = 3549; Asian: N = 1141; Black: N = 5989; White: N = 32832) were assessed at baseline and included in the present study. Clinical status varied from cognitively normal to dementia. The sample was divided into learning and cross‐validation samples; the best fitting model was developed in the learning sample and tested in the cross‐validation sample. Multiple group confirmatory factor analysis (CFA) was used to evaluate measurement equivalence across race/ethnic groups. Measurement invariance models developed in the learning sample were tested in the cross‐validation sample.ResultResults from the full sample identified a best fitting four‐factor model (Figure 1; episodic memory, attention, executive function, language). Multiple group analyses confirmed the presence of metric invariance (Table 2; invariant factor loadings). Results supported partial scalar invariance—all domains had invariant intercepts but also non‐invariant intercepts. Most memory factor indicators had invariant intercepts (5/7). Attention and language had more non‐invariant intercepts. Category fluency, which loaded onto language and executive function factors, was particularly non‐invariant.ConclusionResults showed that the UDS neuropsychological battery measures the same four factors across race/ethnic groups. Crucially, there are important differences in measurement parameters across race/ethnic groups that must be accounted for in studies using these neuropsychological tests as outcomes. The four‐factor model effectively summarizes the comprehensive neuropsychological test battery and could provide a useful tool for studies of cognitive aging and Alzheimer’s disease and related dementias. Importantly, these cognitive factor scores can be used to clarify the influence of lifestyle and psychosocial factors on cognition across these groups.
Default mode network and medial temporal lobe functional connectivity changes with Alzheimer’s disease severity and cognitive impairment in individuals with Down syndrome
Authors: DiProspero Natalie , Sathishkumar Mithra , McMillan Liv , Keator David B. , Doran Eric , Hom Christy , Nguyen Dana , Rosas H. Diana , Lai Florence , Brickman Adam M. , Schupf Nicole , Silverman Wayne , Lott Ira T , Yassa Michael A. 
Published: December 2022

AbstractBackgroundBy age 40, virtually all people with Down syndrome (DS) have sufficient beta‐amyloid and tau pathologies present to meet the criteria for pathological Alzheimer's disease (AD). Determining the timing and location of neurobiological changes caused by AD is critically important for effective intervention within this high‐risk population and more broadly in the general population, but little is known about the brain changes associated with clinical onset of AD in DS. Previous studies in sporadic AD suggest that functional connectivity of the default mode network (DMN) and medial temporal lobe (MTL) is vulnerable to AD pathology‐related impairment.MethodSeventy‐five individuals with DS (mean age 49.9±6.6, 36% women) from a subset of the Alzheimer’s Biomarkers Consortium ‐ Down Syndrome study underwent MRI, including an MPRAGE scan and a resting state functional scan. Participants completed a battery of neuropsychological tests and were assigned a consensus diagnosis for the presence or absence of mild cognitive impairment (MCI‐DS) or AD dementia. Forty‐eight participants were classified as cognitively stable (CS) (mean age 48±6.1, 42% women), 16 participants had MCI‐DS (mean age 50.8±4.2, 19% women), and 11 participants had dementia (mean age 57.2±6.6, 36% women).ResultParticipants with dementia had lower functional connectivity between the posterior DMN and the MTL relative to the CS and MCI‐DS groups. MCI‐DS participants had greater functional connectivity within the MTL relative to the CS group. Functional connectivity differences in these networks tracked with memory performance as well.ConclusionChanges in DMN and MTL functional connectivity are related to the progression of clinical symptoms of AD‐DS and may reflect synaptic changes stemming from AD pathology.
A matrisomal proteomics network modulates tau and amyloid‐beta toxicity in fly AD models.
Authors: Li‐Kroeger David , Al‐Ramahi Ismael , Marella Aditi , Amoh Bismark K , Smith Nathaniel , Botas Juan , Seyfried Nicholas T. , Levey Allan I. , Shulman Joshua M 
Published: December 2022

AbstractBackgroundMounting evidence indicates Alzheimer’s disease (AD) has a complex etiology where insults in multiple pathways conspire to disrupt neuronal function, yet the molecular changes underlying AD remain poorly understood. To identify protein changes associated with AD, we previously performed mass‐spectrometry on post‐mortem brain tissue from longitudinal cohorts and identified >40 protein coexpression networks correlated to AD pathological and clinical traits. A small module (M42) consisting of 37 proteins linked to the extracellular matrix (ECM/matrisome) has the strongest correlation to AD pathology (r=0.75), and includes several proteins linked to AD (e.g. APP, APOE) including SMOC1 as the central hub. SMOC1 has conserved roles in modulating TGF‐Beta and wnt signaling during development, however, its role in the adult brain remains unstudied.MethodWe evaluate the SMOC1 associated protein network using the powerful genetics of Drosophila to characterize its role in neuronal function and uncover links to specific triggers of AD. We use a high‐throughput robotic screening platform and video assisted software which enables robust, quantitative assessments of neurological function to identify conserved members of M42 that modify Amyloid‐Beta‐ or tau‐induced neurodegeneration. Using a combination of loss‐of‐function alleles and RNA interference (RNAi) we tested over 200 transgenic fly lines, representing 47 Drosophila genes corresponding to 37 human proteins nominated from the M42 ECM network.ResultWe found that SMOC1 knock‐down modifies tau toxicity using RNAi and loss‐of‐function alleles, confirming a link to specific AD triggers. In addition, we identified 13 other genes with robust evidence of interactions with either tau or Aβ in our fly models including multiple wnt signaling components and TGF‐β ligands. Additionally, we begin characterizating the fly ortholog dSMOC1 showing expression in a small subset of neurons and many glial cells in the brain. Finally, we show human SMOC1 can rescue lethality caused by complete loss of dSMOC1 function, thus setting the stage for mechanistic analysis.ConclusionThe M42 protein coexpression network contains multiple proteins with links to AD and our screening pipeline identified multiple conserved ECM proteins interacting with specific AD triggers. This analysis helps diversify the pool of potential therapeutic targets for the fight to cure AD.
CSF tau phosphorylation at sites 217 and 205 mediate the relationship between PET amyloid and downstream AD markers
Authors: Meeker Karin L. , Barthélemy Nicolas R. , Gordon Brian A. , McDade Eric , Karch Celeste M. , Fagan Anne M. , Strain Jeremy F. , Luckett Patrick H , Benzinger Tammie L.S. , Bateman Randall J. , Holtzman David M. , Ances Beau M ,   the Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2022

AbstractBackgroundAssociations between amyloid and downstream measures of Alzheimer disease (AD) are often lacking. In autosomal dominant AD (ADAD), cerebrospinal fluid (CSF) phosphorylated tau 217 and 181 (pT217 and pT181) increase shortly after amyloid positron emission tomography (PET), followed by tau 205 (pT205), then tau PET. Each site also tracks closely with disease progression and is associated with longitudinal cognitive decline. Collectively these findings lead to the question of which p‐tau sites affect the relationship between amyloid and downstream AD markers (i.e., tau, MRI cortical thickness, Clinical Dementia Rating [CDR] Scale status), and more specifically whether they mediate such associations.MethodCSF tau phosphorylation occupancy on 217, 181 and 205 residues, CSF total tau (t‐tau), amyloid PET, ADAD cortical thickness signature, and CDR status were measured in 150 individuals from the Dominantly Inherited Alzheimer Network (non‐mutation carrier [MC‐]; n=64; and mutation carrier [MC+]; n=86). Three multiple mediation analyses assuming nonlinear relationships were performed with amyloid PET as the predictor variable, CSF p‐tau sites (pT217, pT181, pT205) and t‐tau (when appropriate) as mediators, and either CSF t‐tau, cortical thickness, or CDR status as the outcome variables. For each model, estimated years to symptom onset (EYO), age, sex, and ADAD mutation status were included as covariates. All models were run with 500 iterations to bootstrap confidence intervals.ResultIncreased amyloid PET was associated with elevated CSF pT217, pT181, and pT205 (p’s<0.03). For each model, the effects of amyloid PET on downstream AD markers were jointly mediated by CSF pT217 and pT205. Specifically, elevated CSF pT217 and pT205 were associated with increased CSF t‐tau, decreased cortical thickness, and higher CDR scores (p’s<0.01). CSF t‐tau and pT181 did not mediate these relationships (p’s>0.05).ConclusionElevated pT217 and pT205, but not pT181 or t‐tau, mediate the relationship between amyloid and downstream AD biomarkers in ADAD. AD‐related brain atrophy and clinical status may be dependent on specific tau sites; future mechanistic experiments are needed to fully understand such relationships. These results support the hypothesis that tau phosphorylation at specific sites plays a critical role in the progression and pathogenesis of ADAD, and may be a possible target for future treatments.
Longitudinal pathologic course of older individuals with medial temporal tau deposition in the absence of amyloid‐β pathology
Authors: Costoya‐Sánchez Alejandro , Moscoso Alexis , Silva‐Rodríguez Jesús , Aguiar Pablo , Pontecorvo Michael J. , Devous Michael D. , Schöll Michael , Grothe Michel J. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD)‐like tau pathology in the medial temporal lobe (MTL) is also commonly observed in older individuals without amyloid‐β (Aβ) pathology, a condition termed primary age‐related tauopathy (PART). Little is known about the longitudinal course of this condition and its association with the AD continuum remains controversial. We used serial PET, MRI, and CSF data to study the longitudinal pathologic course of older individuals who show PET‐measured MTL tau pathology in the absence of Aβ pathology.MethodWe included older individuals with varying degrees of cognitive performance from the Alzheimer’s Disease Neuroimaging Initiative, the Harvard Aging Brain Study, and AVID’s A05 Study who had undergone baseline (n=1097) and follow‐up [18F]flortaucipir (FTP) (n=489, follow‐up: 1.83±0.84 years) and Aβ‐PET scanning (n=398, follow‐up: 2.36±0.76 years). Participants were separated into three groups according to Aβ and tau positivity (A‐T‐, A‐T+, A+T+), using a cut‐off of 12 centiloids for A+ and the 95th percentile of entorhinal (ERC) FTP SUVR values in healthy young controls (n=16, ≤39y) for T+. In complementary analyses we also assessed longitudinal changes in CSF biomarkers (n=99, follow‐up: 2.34±1.05 years) and cortical atrophy on MRI (n=650, follow‐up: 2.00±0.86 years).Result43% of A‐ individuals and 81% of A+ individuals were ERC‐tau positive. Cross‐sectionally, A‐T+ showed elevated FTP SUVR restricted to the medial/inferior temporal lobe, while A+T+ displayed a more AD‐characteristic pattern of widespread cortical FTP uptake (Fig. 1A). A‐T+ showed moderate FTP SUVR increases over time largely limited to the temporal lobe, whereas FTP SUVR increases were widespread in A+T+ (Fig. 1B). Notably, A‐T+ individuals did not increase Aβ accumulation over time (Fig. 1C). CSF analysis confirmed longitudinal tau increases in A‐T+ in the absence of increased Aβ accumulation (Fig. 1D). Compared to A‐T‐, A‐T+ individuals demonstrated accelerated MTL atrophy, whereas A+T+ showed more widespread AD‐typical cortical atrophy (Fig. 2).ConclusionElevated MTL tau‐PET signal is frequently observed in older individuals without notable Aβ pathology, reminiscent of pathology‐defined PART. These A‐T+ individuals exhibit a comparably slow course of progressive tau accumulation and neurodegeneration confined to the temporal lobe and do not appear to be on a pathologic trajectory towards AD.
The role of cortical microstructural changes on longitudinal accumulation of tau and cognitive decline in at risk older adults
Authors: Gagliardi Geoffroy Pierre , Rodriguez‐Vieitez Elena , Montal Victor , Sepulcre Jorge , Diez Ibai Palacio , Lois Cristina , Hanseeuw Bernard , Schultz Aaron P. , Properzi Michael J , Papp Kathryn V. , Marshall Gad A , Fortea Juan , Johnson Keith A. , Sperling Reisa A. , Vannini Patrizia 
Published: December 2022

AbstractBackgroundNon‐invasive diffusion‐weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) was recently shown to be cross‐sectionally associated with tau in cognitively‐normal older adults (Rodriguez‐Vieitez et al., Mol. Psych. 2021), suggesting that it might be an early marker of neuronal injury. However, the impact of cMD on longitudinal accumulation of tau pathology is currently unknown. Moreover, APOE‐e4 — the strongest genetic risk factor for sporadic AD — has been shown to be related to tau aggregation (Therriault et al.,JAMA Network 2019) and cognitive impairment in older adults. Here, we investigated whether cMD at baseline can predict longitudinal accumulation of tau as well as cognitive decline in cognitively‐normal adults with and without an APOE‐e4.Methods122 cognitively‐normal participants from the Harvard Aging Brain Study (71.0±9.7 years; 79 women[64.8%]), 30.3% APOE‐e4‐carriers, 16.0±2.9 years of education; Table 1) underwent DWI, T1w‐MRI, 18F‐flortaucipir(FTP)‐PET imaging and cognitive assessments at baseline. All participants had at least one longitudinal follow‐up FTP‐PET scan (average follow‐up time of 2.4±0.55 years). PET data were normalized to cerebellar grey‐matter. FTP‐PET was quantified using PVC‐corrected SUVR. Longitudinal measures of Preclinical Alzheimer Cognitive Composite (PACC5) were available for all individuals over a 7.2±2.4 years follow‐up interval. We assessed whether the interaction of APOE‐e4 and cMD (in entorhinal and inferior‐temporal cortices) was associated with longitudinal local tau accumulation and with longitudinal PACC5 using separate linear mixed‐effects models. Models were corrected for demographics and baseline tau or PACC5 as appropriate.ResultsThe APOE‐e4 carriers and non‐carriers had similar baseline demographics and imaging characteristics (Table 1). We found significant interaction effects of APOE‐e4 status and cMD in predicting longitudinal tau (entorhinal p=0.008 and inferior‐temporal p=0.032) and longitudinal PACC5 (both entorhinal and inferior‐temporal p<0.001), such that baseline cMD predicted the accumulation of tau and cognitive decline in APOE‐e4‐carriers only (Figures 1 and 2).ConclusionsOur results demonstrate that the cortical microstructual changes measured by cMD are related to accumulation of longitudinal local tau and cognitive decline in at‐risk individuals. The combination of APOE‐e4 and elevated cMD may help identify individuals at short‐term risk of tau accumulation and AD‐related cognitive decline, suggesting utility in therapeutic trials.