bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantifying Extent, the Spatial Distribution of Flortaucipir PET Uptake, in an Autopsy Cohort and its Correspondence to Post‐Mortem Staining of Alzheimer’s Disease Biomarkers
Authors: Kennedy Ian Andrew , Kotari Vikas , Southekal Sudeepti , Pontecorvo Michael J. 
Published: December 2022

AbstractBackgroundIn Alzheimer’s disease, neurofibrillary tangle (NFT) burden can be characterized in postmortem staining and in vivo NFT‐specific flortaucipir PET by increases in intensity and spatial distribution. Previous work compared intensity based standard uptake value ratios (SUVRs) from Early Tau and MUBADA volumes of interest (VOIs) in detecting Braak stage pathology. We propose a measure called Extent to quantify the spatial distribution of NFT‐specific uptake in flortaucipir PET from the Phase III study AV‐1451‐A16 and compare against Early Tau and MUBADA SUVRs in detecting Braak stage pathology and post‐mortem amyloid burden.MethodsThis retrospective analysis of the AV‐1451‐A16 study included 60 subjects that underwent ante‐mortem flortaucipir imaging and post‐mortem assignment of Braak stages and Thal/CERAD scoring for amyloid burden. The processing of the flortaucipir scans and the recording of neuropathological findings were performed as previously described except cerebellum crustaneous was used as a reference region. Extent was calculated by 1) creating a Z‐score image using 16 young cognitively normal controls, 2) retaining voxel clusters with Z‐scores smaller than a false discovery corrected p‐value of 0.01, and 3) calculating the ratio of the number of surviving voxels against the total number of voxels in the mask. Flortaucipir positivity was defined as greater than 2.5 SD of the mean of young controls for Early Tau and MUBADA SUVRs and as non‐zero for Extent. Amyloid positivity was defined by a Thal/CERAD scoring of 2 or higher and compared to flortaucipir positivity using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).ResultsExtent detected subjects with flortaucipir positivity comparably to Early Tau in Braak stages I, II, and III while detecting more subjects with flortaucipir positivity in Braak stages V and VI than Early Tau and MUBADA (Table 1 and Figure 1). For amyloid positivity, Extent had the highest sensitivity (79.62%) and NPV (29.42%) while MUBADA had the highest specificity (87.50%) and PPV (97.06%) (Table 2).ConclusionBased on the Correspondence to post‐mortem staining, the Extent measure of flortaucipir spatial distribution may provide benefit over intensity based SUVRs in detecting flortaucipir and amyloid positive subjects for inclusion in future studies.
Tau PET imaging with 18F‐PI‐2620 in patients with corticobasal syndrome: a case series
Authors: Santibanez Rodrigo A , Mendez‐Orellana Carolina , Juri Carlos , Escobar Sebastian , Bustamante Gabriel , Quiroga Cosme , Contreras Nicolas , Haeger Arlette , Amaral Horacio , Kramer Vasko 
Published: December 2022

AbstractBackgroundCorticobasal syndrome (CBS) is the clinical phenotype originally described for corticobasal degeneration (CBD), a rare sporadic neurodegenerative 4‐repeat tauopathy, clinically characterized by the presence of asymmetric parkinsonism, apraxia, cortical sensory deficits, dystonia, myoclonus, and cognitive dysfunction. However, patients with CBS can have neurodegenerative pathology other than CBD, like progressive supranuclear palsy (PSP), Alzheimer's Disease (AD), Vascular Dementia, and Lewy body dementia. Selective tau tracers have made it possible to detect the presence of abnormal tau deposits in vivo. 18F‐PI‐2620 is a tau‐specific positron emission tomography (PET) tracer with a high binding affinity for aggregated tau. This study aims to investigate the potential role of 18F‐PI‐2620 as a biomarker in patients with CBS.MethodFour participants with clinical features consistent with probable CBS according to the 2013 Armstrong diagnostic criteria underwent dynamic PET scans for 75 min after injection of 18F‐PI‐2620. Specific binding ratios were derived from averaged PET images from 45‐75 min post‐injection.ResultFirst two patients had robust increases in 18F‐PI‐2620 uptake in temporal, parietal, and occipital cortical regions with relative sparing of globus pallidus and putamen. In the third patient, 18F‐PI‐2620 uptake was observed in the globus pallidus and putamen with relative sparing of cortical regions. The fourth patient had low 18F‐PI‐2620 uptake localized in the globus pallidus, temporal, and parietal regions.ConclusionIn the first two patients, 18F‐PI‐2620 binding distribution resembles what was described for Alzheimer's disease. In the third patient, 18F‐PI‐2620 uptake pattern suggests PSP. In this particular case, we hypothesize the definitive diagnosis is PSP‐CBS, a rare clinical presentation of PSP with CBS features. Finally, the fourth patient had low 18F‐PI‐2620 uptake but in areas clearly related to AD, PSP, and probably CBD. Our findings support CBS's heterogeneous pathological basis and suggest that 18F‐PI‐2620 could represent a valuable tool in the assessment of CBS, establishing an underlying tauopathy in most cases. However, we suspect 18F‐PI‐2620 in CBS is insufficient to distinguish, in some cases, AD pathology from other tauopathies. Therefore, the use of additional biomarkers to establish the presence of amyloid pathology should be considered. Further studies are needed to confirm these preliminary results.
Biological characterization with CSF proteomics of dementia with Lewy bodies (DLB) according Alzheimer's disease (AD) biomarker profile
Authors: Vermunt Lisa , Lemstra Afina W. , Doelkahar Brian S , Irwin David J. , van de Beek Marleen , Chen‐Plotkin Alice , van der Flier Wiesje M. , Peeters Carel F.W. , Pijnenburg Yolande A.L. , Tijms Betty M. , Visser Pieter Jelle , del Campo Marta , Teunissen Charlotte E. 
Published: December 2022

AbstractBackgroundIn dementia with Lewy bodies (DLB), Alzheimer co‐pathology is common, and associated with an unfavorable prognosis. For targeted treatment development it is crucial to understand the biological underpinnings of DLB with Alzheimer co‐pathology, and how it differs from Alzheimer disease (AD). We performed a cerebrospinal fluid (CSF) proteome profiling to biologically characterize DLB with and without AD co‐pathology in vivo.MethodPatients from Amsterdam Dementia Cohort, Twin60+, and UPENN, we selected individuals with DLB (n=109), and subcategorized them in CSF Aβ42 (A‐/A+) and pTau‐181 (T‐/T+) biomarker groups (A‐T‐ n=29; A‐T+ n=16; A+T‐ n=29; A+T+ n=36), and patients with AD dementia (A+T+ n=230) and cognitively normal controls (A‐T‐ n=246). CSF levels of 810 proteins were measured with the Olink proximity extension assay. We compared protein profiles from the DLB subgroups and AD dementia with controls with ANCOVA adjusted for age and sex. Proteins with significant FDR‐controlled p‐values were used to perform functional enrichment analyses in KEGG and GO Biology and Cellular components using STRING‐DB.ResultDLB A‐T‐ exhibited least abnormalities compared to controls, with 6 proteins dysregulated (Figure 1). DLB A‐T+ had 12 upregulated proteins. DLB A+T‐ exhibited the most distinct protein dysregulation, with 16 upregulated proteins, and 312 downregulated proteins. DLB A+T+ had 3 downregulated and 18 upregulated proteins. Of the DLB groups, DLB A+T+ had with 15 proteins the largest overlap in dysregulated proteins with AD dementia patients (Figure 1). In functional enrichment analysis for DLB A‐T‐ no enrichment was present. DLB A‐T+ and DLB A+T+ groups were enriched for proteins involved cytokine‐cytokine interactions. The DLB A+T‐ group had top enrichment for basement membrane components and phenylalaline metabolism upregulation, and cell adhesion molecules, VEGF, and axon guidance and morphogenesis downregulation.ConclusionThe CSF proteome in DLB varied depending on the CSF AD profile. The overlap in CSF proteome between AD dementia and DLB with signs of AD seems to cover mostly immune‐mediated processes. The biological abnormalities in DLB with isolated abnormal CSF Aβ42 were most distinct, possibly pointing to a unique subtype. Using biomarkers and proteomics for understanding the biology behind AD co‐pathology could guide treatment development for DLB.
Longitudinal cerebrospinal fluid phosphorylated tau181 and total tau do not reflect tau PET retention in dominantly inherited Alzheimer disease
Authors: McDade Eric , Wang Guoqiao , Li Yan , Gordon Brian A. , Benzinger Tammie L.S. , Fagan Anne M. , Llibre‐Guerra Jorge J , Cruchaga Carlos , Clifford David B. , Xiong Chengjie , Perrin Richard J. , Bittner Tobias , Holdridge Karen C. , Yaari Roy , Bateman Randall J. ,   Dominantly Inherited Alzheimer Network
Published: December 2022

AbstractBackgroundAlthough Alzheimer disease (AD) related changes of tau can be measured in fluids and by positron emission tomography (PET), it remains unclear how these two are associated across the AD spectrum. To further explore the association between soluble tau related biomarkers‐ cerebrospinal fluid (CSF) total tau and p‐tau181‐ and neurofibrillary tangles (NFT) (flortaucipir PET), we compared longitudinal change of each in the dominantly inherited AD trials unit (DIAN‐TU) trial of solanezumab and gantenerumab.Method73 Mutation carriers (MC) (31 CDR>0) from the DIAN‐TU‐001 study (30 gantenerumab, 20 solanezumab, 23 shared placebo) underwent longitudinal collection of CSF for measurement of p‐tau181 and total tau, and flortaucipir tau PET over 2.3 (0.92) mean (SD) years; tau PET was available at baseline for 26% of participants. Individual rates of change for CSF measures and tau PET retention were estimated using the method of least squares. Spearman correlations of the rate of change were used to assess the association between CSF and tau PET.ResultFor all MCs the change of CSF p‐tau181 and tau had no association with change in tau PET standard uptake value ratio SUVR (r = 0.01, p‐0.95 and r = 0.10, p‐0.43), figure. When limiting the correlations to those in the gantenerumab arm, where a significant reduction in p‐tau181 and total tau was previously identified, there remained no clear association between a reduction in soluble tau measures in CSF and change in tau PET SUVR (r=‐0.21, p‐0.27 and r= ‐0.08, p‐0.71).ConclusionIn dominantly inherited AD, soluble p‐tau181 and total tau changes in CSF appear to reflect disease processes that are distinct from the change in NFT pathology measured by tau PET. These results suggest the need for caution in extrapolating treatment related changes of soluble tau to those of NFT pathology.
Brain metabolism changes in middle‐aged asymptomatic APOE‐ε4 carriers. The PESA Study
Authors: Tristão‐Pereira Catarina , Toribio‐Fernández Raquel , Sanchez‐Gonzalez Javier , Gispert Juan Domingo , Ibañez Borja , Cortes‐Canteli Marta , Fuster Valentin 
Published: December 2022

AbstractBackgroundApolipoprotein E (APOE) is the major genetic risk factor for late‐onset Alzheimer’s disease (AD) and is implicated in cardiovascular disease. TheAPOE‐ε4 allele is associated with brain hypometabolism in AD, mild cognitive impairment (MCI) (Mosconi et al. Neurology 2004) and in cognitively unimpaired middle‐aged individuals (Reiman et al. NEJM 1996). Greater longitudinal decreases in brain metabolism were reported in APOE‐ε4 carriers with MCI (Paranjpe et al. Neuroimage Clin 2019), but studies on brain metabolism longitudinal changes in unimpaired middle‐aged APOE‐ε4 carriers are scarce and with relatively small sample sizes (Reiman et al. PNAS 2001). The Progression of Early Subclinical Atherosclerosis (PESA) study is a longitudinal study following >4000 asymptomatic middle‐aged subjects deeply screened for cardiovascular risk factors (CVRFs) (Fernandez‐Ortiz et al. AHJ 2013). Individuals with the highest burden of atherosclerosis underwent FDG‐PET at baseline and CVRFs were associated with hypometabolism in AD regions (Cortés‐Canteli & Gispert et al. JACC 2021). Those individuals underwent a 6‐year follow‐up FDG‐PET. Here, we investigate the effect of APOE genotype on brain metabolism progression in middle‐aged asymptomatic individuals.Method365 cognitively unimpaired adults (mean age 50 years old) were genotyped for APOE and underwent two FDG‐PET studies (Table). Baseline and follow‐up images were spatially normalized to a group template in the MNI space. FDG‐uptake was normalized to the pons and images were subtracted, yielding a measure of brain metabolic change. An ANOVA model was carried out to compare brain metabolism change between APOE‐ResultAt the global level, we observed significantly greater decreases in FDG uptake in ε4 carriers compared to the reference ε3/ε3 genotype (p=0.024). Voxelwise analysis showed greater decreases between ε4 carriers and non‐ε4 carriers in the precuneus, supramarginal gyrus, hippocampus and anterior cingulate gyrus (Figure).ConclusionAsymptomatic middle‐aged APOE‐ε4 carriers have a greater decline in brain metabolism in regions known to display hypometabolism in AD, suggesting an increased vulnerability. Further analysis will reveal the extent to which AD pathology and/or other risk factors may mediate this association.
MIND diet associated with less hippocampal sclerosis: A Community‐Based Neuropathologic Study
Authors: Agarwal Puja , Agrawal Sonal , Cherian Laurel J , Aggarwal Neelum T. , James Bryan D , Holland Thomas Monroe , Bennett David A , Barnes Lisa L. , Leurgans Sue E. , Schneider Julie A 
Published: December 2022

AbstractBackgroundMediterranean‐DASH Intervention for Neurodegenerative Delay (MIND) diet is associated with slower cognitive decline, reduced Alzheimer’s dementia risk, and greater brain volume. We have also shown MIND diet is associated with less Alzheimer’s disease (AD) pathology. Hippocampal sclerosis (HS, severe neuronal loss and astrogliosis in CA1/subiculum), is increasingly recognized as an important pathologic finding associated with TDP‐43 (“LATE‐NC), AD pathology, and dementia. The pathogenesis of HS is not clear but may be neurodegenerative and/or vascular. This study investigates the association of the MIND diet with hippocampal sclerosis in autopsied brains from a community sample.MethodsThe study was conducted among 581 deceased participants (age at death = 91.3 ± 6.1 years; 72% female, education = 14.8 ± 2.8 years) of the Rush Memory and Aging Project. The coronal section of the mid hippocampus CA1 and subiculum were assessed for severe neuronal loss and gliosis to define HS. Mean MIND diet scores were obtained from a validated food frequency questionnaire administered annually during follow‐up years prior to death. We used logistic models adjusted for age at death, sex, education, and total calories to examine associations of MIND diet (continuous and grouped in tertiles) with HS. Further models controlled for APOE‐ε4 status, and other pathologies including global AD pathology, arteriolosclerosis, and LATE‐NC stage.ResultsHigh and moderate adherence to MIND diet was associated with 69% (OR (95% CI) = 0.31(0.15, 0.64)) and 54% (OR (95% CI) = 0.46 (0.24, 0.79)) lower odds of HS. After adjusting for APOE‐ε4 status and AD pathology, the association was retained (T3 vs. T1: OR (95% CI) = 0.30 (0.15, 0.62); T2 vs. T1: (95% CI) = 0.46 (0.24, 0.87); p for trend = 0.0007). Further adjusting for arteriolosclerosis and LATE‐NC did not appreciably change the effect estimates.ConclusionThe MIND diet is associated with a lower likelihood of hippocampal sclerosis. Further studies are needed to more fully understand the role of diet on hippocampal structure and function in the context of AD and related brain pathologies.
Global brain venous oxygenation is associated with cardiorespiratory fitness in older adults
Authors: Green Zachary D. , John Casey S. , Brooks William M , Lee Phil , Burns Jeffrey M. , Morris Jill K. 
Published: December 2022

AbstractBackgroundT2‐Relaxation‐Under‐Spin‐Tagging (TRUST) is an MRI technique which allows for the measurement of brain blood oxygenation. Global venous oxygenation has been shown to decrease over the course of life and may prove useful as a measure of brain aging. No studies to date have examined the association between cardiovascular fitness and brain venous oxygenation.MethodGlobal venous oxygenation (Yv) and cardiorespiratory fitness were measured in sixteen older adults. Yv was measured from voxels within the superior sagittal sinus (SSS) using the TRUST sequence. The four voxels with the highest measured signal had their intensities averaged within each volume of the sequence. These values were fitted to an exponential function to yield a quantitative T2 and an estimate of Yv. Cardiorespiratory fitness was measured as the VO2 peak (mL/kg/min) during a cardiopulmonary exercise test to maximal capacity or volitional termination following the Cornell modified Bruce protocol.ResultUsing a linear regression with age and sex as covariates (F = 4.410, p = .31), Yv was shown to associate significantly with peak VO2 (b = .444, p = .020). Yv did not differ between male and female participants (t = 1.758, p = .101), and did not appear to associate independently with age (R = .182, p = .499). However, our sample was small and only included older adults.ConclusionThis study shows for the first time that whole body cardiorespiratory fitness is associated with global brain venous oxygenation. Future work will examine the utility of this neuroimaging biomarker to monitor changes in fitness with measures of cognitive aging
SORL1 regulates the generation of APOE selectively in human neurons
Authors: Lee Hyo , Aylward Aimee J , II Richard V Pearse , Hsieh Yi‐Chen , Augur Zachary M , Knupp Allison , Goberdhan Srilakshmi , Pan Cheryl , Seyfried Nicholas T. , Bennett David A , De Jager Philip L , Young Jessica E. , Young‐Pearse Tracy 
Published: December 2022

AbstractBackgroundSORL1 is a neuronal sorting receptor that has been strongly implicated in the pathogenesis of Alzheimer’s disease (AD). While SORL1 has structural similarities to low‐density lipoprotein (LDL) receptors, it is unclear if it plays a role in regulating lipoprotein levels in the brain. We aimed to utilize human induced pluripotent stem cells (iPSCs) to understand the intersection of SORL1 and APOE biology and interrogate the potential role of SORL1 as an LDL receptor.MethodWe differentiated iPSC lines derived from the ROS and MAP cohorts that span the cognitive and neuropathological spectrum of aging to neuron and astrocyte fates and performed unbiased proteomic profiling, Western blotting, and ELISA to quantify protein levels of SORL1 and APOE. We next used CRISPR/Cas9 to generate SORL1 null iPSC lines and differentiated to neuron, astrocyte, and microglial fates. In neurons and astrocytes, AD‐relevant phenotypes such as APOE, Abeta, and phospho‐tau were assessed. Rescue experiments were performed in SORL1 KO neurons using pharmacological perturbations and shRNA to elucidate the pathways downstream of loss of SORL1 that lead to altered Abeta, tau and APOE.ResultWe observed a strong correlation between SORL1 and APOE protein expression in neurons derived from ROSMAP cohort individuals that was not apparent in astrocytes. Next, we validated previously reported findings that loss of SORL1 in neurons results in an elevation in Abeta levels. We expanded upon these findings to show that SORL1 null neurons display elevated phospho‐tau levels and a significant reduction of extracellular and intracellular APOE. While enhancing retromer and autophagy function rescued the elevation of phosphorylated tau in SORL1 null neurons, these treatments did not rescue reduced APOE levels. Rather, loss of SORL1 resulted in a reduction in APOE RNA expression, suggesting that loss of SORL1 leads to a downregulation of APOE at the transcriptional level. Integration of profiling data from ROSMAP iNs and SORL1 knock out iNs implicate the transcription factors NFkB and REV‐ERB as potentially mediating the effect of loss of SORL1 on APOE RNA levels.ConclusionSORL1 has a neuron‐specific function in regulating APOE levels that is separable from its role in regulating Abeta and phospho‐tau levels.
In vivo downregulation of pancreatic amylin improves brain function and reduces brain β amyloid pathology in APP/PS1 mice
Authors: Viswanathan Velmurugan Gopal , Kotiya Deepak , Verma Nirmal , Despa Florin 
Published: December 2022

AbstractBackgroundAmylin is a systemic hormone that is co‐secreted with insulin from pancreatic β‐cells. Amylin co‐aggregates with brain parenchymal and vascular b‐amyloid in persons with Alzheimer’s dementia. Cross‐sectional data show higher CSF and blood amylin levels are associated with increased frequency of cognitive impairment. The present study sought to determine how in vivo downregulation of amylin influences brain function during the development of Aβ pathology.MethodBecause mouse amylin is nonamyloidogenic, we developed an APP/PS1 mouse model in which the mouse amylin gene is replaced by the human amylin gene and is conditionally regulated by tamoxifen (TMX) injection, intraperitonially. At 3 months of age, human amylin‐expressing male mice were randomly assigned to either amylin downregulation group or control group (maintained amylin expression) (n = 10/group). Two months later, we assessed brain function with the novel object recognition test and performed comparative immunochemical Aβ analyses of hippocampal tissue by using MSD ELISA and immunohistochemistry (IHC).ResultMice with downregulated human amylin show enhanced recognition memory index (p < 0.001) and lower plasma amylin levels (p < 0.001) compared to those that continued to express human amylin. This was associated with decreased hippocampal levels of Aβ42 (p < 0.05) measured by MSD ELISA and decreased number of plaques (P < 0.01) measured by IHC.ConclusionAmylin downregulation in APP/PS1 mice improves memory. Molecular processes associated with improved memory involve decreased hippocampal Aβ pathology. Further studies are needed to understand how altered secretion of pancreatic amylin may influences the balance between brain Aβ accumulation and Aβ elimination from the brain.