bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diverse patterns of Tau radiotracer binding progression in Alzheimer’s disease: A two‐year tau PET imaging study
Authors: Lagarde Julien , Olivieri Pauline , Tonietto Matteo , Gervais Philippe , Caillé Fabien , Moussion Martin , Bottlaender Michel , Sarazin Marie 
Published: December 2023

AbstractBackgroundPositron emission tomography (PET) imaging enables the in vivo detection of amyloid and tau pathologies. The longitudinal progression of [18F]‐flortaucipir PET imaging could be of interest to better understand the spatial and temporal relationships between tauopathy, cortical atrophy, and the cognitive decline.MethodWe explored the longitudinal progression of the tau radiotracer binding and of cortical atrophy over 2 years in a cohort of 27 prodromal/mild AD patients (positive CSF biomarkers and amyloid‐PET) compared with twelve amyloid‐negative controls. All subjects underwent a complete neuropsychological assessment, 3T brain MRI, [11C]‐PiB and [18F]‐flortaucipir PET imaging (Tau1), and were monitored annually over 2 years, with a second brain MRI and tau PET imaging (Tau2) after 2 years. We studied the longitudinal progression of tau radiotracer binding (Tau2‐Tau1) in AD patients and used mixed effects models to explore the relations between the progression of tau binding or cortical atrophy and cognitive decline.ResultWe found an average longitudinal increase in tau radiotracer binding in most cortical regions, especially in the frontal cortex, but an average decrease in the lateral temporoparietal cortex. In this region, individual analyses revealed two distinct evolutions of tau radiotracer binding according to Tau1 uptake: low‐Tau1 AD patients (SUVr<1.6) demonstrated an increase in tau radiotracer uptake in all cortical regions and a slow clinical progression, whereas high‐Tau1 patients demonstrated a paradoxical plateauing or decrease of tau tracer uptake in the temporoparietal cortex and a faster clinical progression. Cognitive decline was weakly associated with Tau2‐Tau1, but strongly associated with the regional cortical atrophy progression.ConclusionOur results suggest that tau PET imaging could detect patients with a “more aggressive” biological form of AD characterized by high temporo‐parietal Tau1 binding. In these patients, the decrease of temporo‐parietal tau tracer binding over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. This information may be considered to improve the design of clinical trials and the definition of the neuroimaging outcomes (choice of the tau‐PET regions of interest, consideration of the evolution of cortical atrophy as a reliable reflection of the clinical progression).
Cognitive Health and Functional Abilities of Illiterate Older Peruvians
Authors: Caipa Maritza Pintado , Lanata Serggio , Custodio Nilton 
Published: December 2023

AbstractBackgroundThe demographic changes are clearly affecting developing countries like Peru. Is estimated that approximately 7% of the population in the capital city of Lima, Peru, lives with dementia but there is no knowledge of the cognitive health of illiterate older in urban and rural communities outside Lima, where 41.5% of older adults living in these communities are illiterate. On the other hand, Peru is home to tremendous social and geocultural diversity, which may mitigate the worrisome dementia risk. In this respect, it is interesting to note that many older Peruvians remain active preserved and prolonged functional independence in their respective communities for long periods of time. Additionally, in Peru, several brief cognitive tests have been validated in urban cohorts (mostly within Lima) with elementary level education, but, to our knowledge, no brief tests of cognition or functionality have been validated in illiterate Peruvians. These observations raise important research questions that the present pilot proposal seeks to begin investigating.MethodsWe are characterizing the cognitive health and functional abilities of rural and urban illiterate older adults living in two geoculturally‐distinct regions of Peru, the Andean and Amazonian regions. Within the Andes region, we are studying a cohort of illiterate older adults living in the urban area of Cuzco and another cohort from the rural area of Pomacanchis ‐ Cuzco; within the Amazon region, we will study a cohort of illiterate older adults living in the urban area of Iquitos and another cohort from the rural area of San Reyes. We are conducting a gold standard neurological, neuropsychological, and functional evaluations in all enrolled participants in each of the four cohorts and these will be used to arrive at a multidisciplinary consensus diagnosis of suspected normal aging, subjective cognitive impairment, mild neurocognitive disorder (or mild cognitive impairment), or major neurocognitive disorder (or dementia). We are correlating these diagnoses with results of brief cognitive tests and a brief functionality assessment, the MMSE, RUDAS, the BHA ‐ TabCAT, and the adapted version of PFAQ.Results
In collection process
ConclusionThis pilot project represents the initial steps towards addressing these hypotheses and will generate unique data.
Molecular MRI Identifies Sexually Dimorphic AD Pathology in 3x Tg‐AD Mice
Authors: Parekh Parag A , Badachhape Andrew A , Menon Renuka , Bhavane Rohan , Srivastava Mayank , Sun Xianwei , Bhandari Prajwal , Devkota Laxman , Tanifum Eric , Ghaghada Ketan , Devaraj Sridevi , Annapragada Ananth 
Published: December 2023

AbstractBackgroundWomen exhibit higher prevalence of Alzheimer’s disease (AD) with faster cognitive decline compared to men, but the mechanisms of this dimorphism remain understudied. Astrocyte function and morphology is distinct in some regions of male and female adult brains which may reflect different courses taken by the neurodegenerative process. Additionally, the p‐tau levels are higher in females than in males. The 3xTg AD mouse model, which manifests amyloid and tau pathology, has been reported to exhibit similar sexual dimorphism. In this work, we investigated whether molecular MRI using a targeted agent that detects hyperphosphorylative cells expressing cell‐surface vimentin predominantly on neurons and the disease associated astrocytes in early states of tau pathology can be used for in vivo imaging of sexual dimorphism in AD pathology.MethodLiposomal Withaferin nanoparticles (WNP) that contain Gd/DOTA for an MRI readout were injected in 3xTg AD mice, at 2‐,5‐,7‐ 9‐ and 12‐ months of age. Animals (n = 14/timepoint, 7 males and 7 females) underwent contrast enhanced magnetic resonance imaging (MRI) using T1 weighted sequences to visualize hyperphosphorylative cells expressing cell surface vimentin. Animals were euthanized after the final time point and brains were harvested for histology and immunofluorescence analysis. CE‐MR images were analyzed for signal enhancement.ResultIn this study, we report the sexually dimorphic nature of the cell surface vimentin expressed by the hyperphosphorylative cells in the brain using the 3xTg AD mice. Both sexes were imaged at 2‐,5‐,7‐ and 9‐ months of age to reveal significant differences in the expression of VIM in males and . Signal enhancement in post‐contrast MRI scans over the baseline scans showed significantly higher enhancement in the females compared with the males (p<0.05) Simultaneously, we also investigate the plasma concentrations of total tau, ptau181, amyloid beta 40 and 42.ConclusionFemale mice expressed higher vimentin in comparison with males, thus reflecting changes in the neurodegenerative processes in the brains of females and males of this strain. Sexually dimorphic molecular changes were successfully visualized by molecular MRI.
Phosphatases Pathways as a Potential Lithium Therapeutic Target in Alzheimer’s Disease: Preliminary Results
Authors: Paiva Iara Ribeiro , Forlenza Orestes Vicente , De‐Paula Vanessa V.J. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease, that apart from the classical pathological findings in neurons (neurofibrillary tangles and amyloid plaques), it is known that astrocytes and microglia play an important role leading to a pro‐inflammatory state (Heneka et al, 2015). Post‐translational modifications are major regulators of this response, notably phosphorylation. In this regard, lithium is a drug known for its neuroprotective effects due to inhibition of GSK3β (Forlenza et al, 2012; Rocha et al., 2021). Thus, we aimed to characterize by Gene Ontology (GO) the signaling pathways related to tau phosphatases to further evaluate them in response to lithium.MethodA systematic literature search ascertained thirteen phosphatases (Ppp1cb, Ppp2r2d, Ppp1r1a, Ppm1b, Ppp5c, Ptpn5, Pten, Ptpn11, Ptpn13, Dusp1, Dusp6, Dusp22, Ppp2r4) (Braithwaite et al, 2012; Kerr et al, 2006; Kim et al 2019; Wang et al, 2017; Arango‐Lievano et al, 2016; Banzhaf‐Strathmann et al, 2014; Sanchez‐Mut et al, 2014; Luo et al, 2013). We obtained an enriched network of 50 interactions from these selected seed proteins in STRING, a database of documented and predicted protein‐protein interactions (PPI), using a confidence score of 0.7. Dusp22 and Ppm1b were removed due to lack of connection. From this network, we obtained a list of 63 proteins. Using a 0.001 false discovery rate and a 0.7 strength cut off, we reached 321 biological processes, 49 molecular functions and 39 cellular components. Ethical committee (1666/2021).ResultGO study favored specific pathways on the biological process domain. Among these pathways, the most significant were “activation of mapk activity”, “interferon‐gamma‐mediated signaling pathway”, “response to tumor necrosis factor”, “cellular response to oxidative stress” and “cellular response to cytokine stimulus”. The analysis of the ontological pathways relating the hippocampal tissue with the biological pathways found is in progress.ConclusionThe pathways identified by GO analysis are related to AD pathogenesis, particularly the mapk cascade as a regulator of pro‐inflammatory response. Therefore, understanding these pathways is essential as they are candidates for therapeutic targets for the disease.
Proteo‐genomics of soluble TREM2 in cerebrospinal fluid provides novel insights for TREM2 biology and identifies novel modulators for Alzheimer’s disease
Authors: Wang Lihua , Nykanen Niko‐Petteri , Western Daniel , Gorijala Priyanka , Timsina Jigyasha , Marquié Marta , Boada Mercè , Alvarez Ignacio , Aguilar Miquel , Pastor Pau , Ruiz Agustin , Hohman Timothy J. , Wyss‐Coray Tony , Sung Yun Ju , Cruchaga Carlos ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI),   Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2023

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer’s disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). Here, we pursued the largest CSF study to identify additional novel genetic modifiers of sTREM2.MethodWe performed the genome‐wide association study (GWAS) of CSF sTREM2 in 3350 individuals of European ancestry from eight cohorts. To identify functional genes, we performed multi‐ethnic fine mapping with 250 non‐European individuals. Functional validation using peripheral blood mononuclear cell‐derived macrophages was performed. Colocalization and Mendelian randomization (MR) was performed for the causality of sTREM2 in AD.ResultThe known MS4A locus and three novel loci were identified at genome‐wide significance. In the MS4A locus, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drove the association through multi‐ethnic fine mapping. They showed an epistatic effect for sTREM2 and AD risk. The novel TREM2 locus on chromosome 6 contained two rare missense variants (rs142232675 p.D87N, P = 2.71×10‐10; rs75932628 p.R47H, P = 7.16×10‐19) associated with sTREM2 and AD risk. Another novel locus in the intergenic region between TGFBR2 and RBMS3 (rs73823326, P = 3.86×10‐9) included a regulatory variant with a microglia‐specific chromatin loop for promoters of TGFBR2. Using cell‐ based assays we demonstrate that TGFBR2, but not RBMS3, modify sTREM2 levels. The last novel locus NECTIN2 on chromosome 19 (rs11666329, P = 2.52×10‐8) was independent of APOE genotype and colocalized with cis‐eQTL of NECTIN2 in the brain cortex and cis‐pQTL of NECTIN2 in CSF (PP.H4 = 0.83). This variant was also associated with AD risk (P = 1.52×10‐66) and age at onset (P = 3.26×10‐5). Our MR results confirmed the significant protective effect of sTREM2 on reducing AD risk.ConclusionTo our knowledge, this is the largest study to date aiming at identifying genetic modifiers of CSF sTREM2. We provided novel insights for MS4A and TREM2, the two well‐ known gens for AD risk. We also identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology. Our findings provide new insight to unravel sTREM2 modulators and their role in AD.
Mechanisms linking proteins and structural brain integrity to biological markers of Alzheimer’s Disease
Authors: Turnbull Adam , Kim Yejin , Zhang Kai , Mao Tianrui , Jiang Xiaoqian , Henderson Victor , He Zihuai , Lin Feng Vankee Vankee , Lin Feng Vankee Vankee 
Published: December 2023

AbstractBackgroundMedial temporal lobe (MTL) networks, including posterior‐medial (PM) and anterior‐temporal (AT) subnetworks, are early affected by Alzheimer’s disease (AD) pathologies (tau, neurodegeneration) and are critical for memory, which declines in AD. The biological pathways linking AD pathology, changes in MTL‐AT‐PM structural connectivity (SC), and cognitive decline, are unknown. Plasma protein levels reflect those in the cerebrospinal fluid, providing a low‐invasive potential means of understanding molecular brain changes that occur in AD. These measures may help explain how AD pathology, MTL‐AT‐PM SC, and cognitive decline are linked at the molecular level. We used predefined aging‐related plasma proteins from a meta‐analysis to explore links between MTL‐AT‐PM SC, AD pathologies, and cognitive decline.MethodMTL‐AT‐PM SC scores and plasma protein levels from 100 participants (Stanford ADRC: mean age = 73.7y, 82 healthy control, 16 mild cognitive impairment, and 2 AD) were entered into an Coupled tensor and matrix factorization algorithm, generating clusters based on shared SC‐protein variance. Linear regression analyses were conducted to evaluate cluster relationships with domains of AD (memory, plasma tau, and neurodegeneration by plasma NfL and cortical thickness index).ResultTwo (out of 12 total) SC‐protein clusters significantly related to both tau and neurodegeneration. Both had similar highly contributing proteins (TNFRSF1B.3152.57.1, TNFRSF1B.8368.102.3, GRN.4992.49.1, TNC.4155.3.2, RPS3A.5484.63.3, CD163.5028.59.1, EFNA4.2614.28.2) and SC regions (bilateral: hippocampus, and left: parahippocampal cortex, precuneus, thalamus, and isthmus cingulate). Hippocampal laterality (bilateral vs. opposite directions for left vs. right) and the direction of their relationship to tau/neurodegeneration differentiated these clusters. A 3rd cluster was uniquely associated with composite memory (SC: bilateral: lateral occipital and parahippocampus, left: inferior temporal and hippocampus; proteins: EGFR.2677.1.1, SFRP1.3221.54.1, FAS.9459.7.3, ERBB3.2617.56.35, CFD.13678.169.3, LRP1.8601.167.3, and LPO.4801.13.3).ConclusionProtein‐SC clusters showed both overlapping and unique associations to AD‐associated memory, tau, and neurodegeneration. Two clusters centered on the hippocampus and proteins related to inflammation showed relationships to both tau and neurodegeneration, suggesting they may be important for linking these two aspects of AD pathology. A memory‐related cluster was dominated by neurogenesis related proteins, and occipital/parahippocampal cortex. These findings suggest molecular pathways may differentially affect the left vs. right hippocampus, and AD‐associated pathologies vs. cognition.
Anosognosia is associated with increased prevalence and faster development of neuropsychiatric symptoms in Mild Cognitive Impairment
Authors: Wang Sharon , Gagliardi Geoffroy Pierre , Mimmack Kayden J. , Cacciamani Federica , Elnemais Michael , Munro Catherine E , Gatchel Jennifer , Marshall Gad A , Vannini Patrizia 
Published: December 2023

AbstractBackgroundBoth the loss of awareness for cognitive decline (a.k.a anosognosia) and neuropsychiatric symptoms (NPS) are commonly seen in patients with Alzheimer’s disease (AD) dementia, even in the prodromal stages. Anosognosia and NPS may negatively affect caregiver burden and patient’s activities of daily living. Despite the high impact of these symptoms on patients and their caregivers, our knowledge of how they develop across the AD spectrum is limited. Here, we explored the cross‐sectional and longitudinal associations between anosognosia and NPS in individuals with mild cognitive impairment (MCI).MethodWe included 310 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with a baseline Clinical Dementia Rating global score of 0.5. Everyday Cognition (ECog) questionnaire scores were used to measure complaints from participants and study‐partners at baseline and annually over a mean of 4 years (SD = 3). Anosognosia was defined as the study‐partner having an ECog score ≥2.5/4 and the participant having an ECog score ≤2.5/4 on their baseline measure and their last observation and without having more than 2 consecutive deviating observations during the follow‐up period. The 12 study‐partner‐rated Neuropsychiatric Inventory items determined the presence or absence of specific NPS (see Table 1). The Mini‐Mental State Examination (MMSE), an assessment used to screen for cognitive impairment, was administered annually. Survival analyses were performed to analyze the rate of appearance of NPS over time in individuals with and without anosognosia.ResultSixty participants displayed anosognosia, while 250 did not. At baseline, groups had similar lengths of follow‐up. Participants with anosognosia had lower MMSE scores and a higher proportion of amyloid positivity (see Table 1). At baseline, the frequency of agitation and disinhibition was higher in the anosognosia group. Survival analyses showed earlier onset of all NPS in the anosognosia group (see Figure 1). Specifically, aberrant motor behavior, irritability, disinhibition, apathy, agitation, and hallucinations were highly significant.ConclusionLoss of awareness for cognitive decline is associated with greater frequency and faster onset of NPS over time in participants with MCI. These results support the hypothesis of a potential common underlying neurophysiological process, a finding that needs to be addressed further in future studies.
Mitochondrial DNA variants and Cognitive Function
Authors: Odden Michelle , Li Yongmei , Jotwani Vasantha , McGeever Lea , Jones Robyn , Desprez Pierre‐Yves , Tranah Gregory J. 
Published: December 2023

AbstractBackgroundMitochondrial dysfunction is a hallmark of aging and manifests in age‐associated disorders, including neurodegenerative diseases. Previous work on mitochondrial DNA variants and neurocognitive outcomes has been limited to known variants of interest.MethodWe sequenced the mitochondrial genome in buffy coat samples from two studies, LIFE (Lifestyle Interventions and Independence for Elders) and HABC (Health Aging and Body Composition), and examined the association of shared common variants and cognitive function, after adjustment for 10 principal components to account for population stratification. Participants included self‐reported Black (n = 229 in LIFE and 393 in HABC) and White (n = 1134 in LIFE and 395 in HABC) adults aged ≥ 70 years. Cognitive function was measured by the digit‐symbol substitution test (DSST), a measure of processing speed, and the Modified Mini‐Mental State Exam (3MSE), a measure of global cognition.ResultThere were 96 variants which had a minor‐allele frequency ≥5% in both studies. There were 8 variants associated with DSST in White participants LIFE at the p<0.05 level and 1 at the Bonferroni‐adjusted level (m16223ct). Four reached statistical significance at the p<0.05 level in meta‐analyses of LIFE and HABC (m16223ct, m16093tc, m10873tc, m3106cnc). There were 7 variants associated with 3MSE in White participants in LIFE at the p<0.05 level and none at the Bonferroni‐adjusted level. One reached statistical significance at the p<0.05 level in meta‐analyses of LIFE and HABC (m10873tc). In Black participants, the variants had differential associations with the cognitive outcomes by study, and no associations reached statistical significance after Bonferroni correction or in meta‐analysis. The 4 variants of interest in White participants are located in the 1) hypervariable region 1 of the D‐loop (m16093tc, m16223ct), 2) gene MT‐ND4 coding for subunit ND4 of complex 1 (m10873tc), and 3) gene MT‐RNR2 coding for the 16S ribosomal RNA (m3106cnc).ConclusionPrevious work has identified associations between m16223ct and hippocampal sclerosis and endurance capacity; and ND4 variants and Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Leigh’s disease. In addition, the m10873tc ND4 coding variant is a defining mutation for European Haplogroup N. Mitochondrial genetics may contribute to cognitive health. More research is needed on mitochondrial genetics among Black individuals.
Feature extraction by orthonormal projective non‐negative matrix factorization and longitudinal association between brain atrophy patterns and Alzheimer’s disease
Authors: Shui Lan , Shibata Dean , Chan Kwun Chuen Gary , Haynor David R. 
Published: December 2023

AbstractBackgroundOrthonormal projective non‐negative matrix factorization (OPNMF) was a recently developed approach for feature extraction techniques of neuroimaging data. However, there has been few studies applying this to brain MRI to better characterize the anatomic changes seen in Alzheimer’s Disease (AD) and correlate these patterns with cognitive changes.MethodWe applied OPNMF with refinement to identify distinct spatial components of voxel‐wise volume loss in the structural MRI (3D T1 MPRAGE images) of subjects with AD (N = 109, mean age = 74.6 (7.9), ADNI2) relative to healthy young controls (N = 104, mean age = 24.0 (2.9), ABIDE1). Non‐negative least squares (NNLS) was then used to extract non‐negative coefficients representing subject‐specific quantitative measures of regional atrophy. This calculation of coefficients was extended to images not used for component discovery which also included Mild Cognitive Impairment (MCI) and controls. To investigate the cross‐sectional and longitudinal associations between cognitive assessments scores and regional atrophy severity in different diagnostic groups, we used multiple linear regression models and liner mixed‐effects models with random intercepts and slopes controlled for age, sex, educational level, APOE ε4 genotypes were utilized. A validation analysis was performed using ADNI3 images.ResultWe derived 6 atrophy components upon the same training set and there was a sharp decrease in the magnitude of the reconstruction error gradient when moving from 5 components to 6 components, and the components have meaningful interpretation. In the whole cohort, atrophy in 5 of the 6 regions was significantly associated with all three cognitive scores. There is evidence of overall positive trends between diagnosis group and atrophy severity changing rate in all 6 regions. The increased atrophy in all 6 regions was associated with decreases in MMSE and MOCA scores and increases in CDRSB scores in the whole cohort as well as in LMCI cohort. From the validation analysis, we showed that our result from OPNMF is stable in atrophy pattern discovery.ConclusionWe developed a robust pipeline for detecting spatially distinct atrophy components in AD and associated these atrophy patterns with cognitive changes which may help us better characterize the underlying pathology of types of AD and other dementias on MRI.