bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amyloidosis at Putamen Predicts Vulnerability to Alzheimer’s Disease
Authors: Yang Zhengshi , Cummings Jeffrey L. , Cordes Dietmar 
Published: December 2023

AbstractBackgroundUsing merely cortical amyloid burden in a binary approach was commonly adopted for determining if an individual is under AD pathology in both clinical trials and basic research. Subcortical amyloid, compared to cortical amyloid, showed a larger inter‐subject heterogeneity, which may provide valuable insights to their vulnerability to Alzheimer’s disease beyond cortical amyloid.MethodA total of 1344 individuals from ADNI database had 18F‐AV45 amyloid PET scans available. Regional AV45 signal was computed by averaging the signal from gray matter voxels in each region and then normalized to the mean signal in the composite reference region [1, 2]. The cortical AV45 was averaged over extensive regions consisting of frontal, anterior/posterior cingulate, lateral parietal, and lateral temporal regions. The AV45 signal in the subcortex, including putamen and caudate, were also computed. Only the participants under AD pathology, determined based on cortical amyloid positivity, were included in the analysis. The association analysis between subcortical AV45 and cognition was conducted before and after adjusting cortical AV45. A linear fitting of cortical AV45 and AV45 at putamen was conducted and participants were categorized into high (HighP), middle (MidP) and low (LowP) putamen amyloid group thresholded with ±0.5 standardized residuals. Statistical analysis was carried out to evaluate the difference of clinical diagnosis, hippocampal volume and APOE e4 genotype. The relevance of amyloid at putamen with the rate of cognitive decline was examined.ResultPutamen, compared to caudate, had a stronger association with ADAS‐cog13 and MoCA, such an association remained exist after adjusting cortical AV45. Despite distinct AV45 at putamen, participants in LowP, MidP and HighP groups had no cortical AV45 difference. The AV45 at putamen was significantly higher in individuals with more e4 alleles (e4 homozygous > e4 heterozygous > non‐ e4) and more advance clinical stages (Dementia > MCI > CN). The individuals with higher AV45 at putamen had smaller hippocampal volume and faster cognitive decline.ConclusionOur finding suggested that amyloidosis at putamen is a valuable imaging marker beyond cortical amyloid in predicting if a participant is more vulnerable to Alzheimer’s dementia.
The role of biofluid markers in predicting near‐term cognitive impairment
Authors: Yakoub Yara , Ashton Nicholas J. , Karikari Thomas K , Montoliu‐Gaya Laia , Schöll Michael , Spreng R. Nathan , Rosa‐Neto Pedro , Soucy Jean‐Paul , Breitner John C.S. , Zetterberg Henrik , Blennow Kaj , Poirier Judes , Villeneuve Sylvia 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) has been defined as a biological construct that can be determined using in vivo biomarkers. Recent studies confirmed the clinical value of the AT(N) framework when using Aß and tau positron emission tomography (PET) scans in predicting progression from cognitively unimpaired to MCI. Our study aims to investigate if plasma biomarkers can yield similar predictive performance to PET biomarkers, and to also compare against cerebrospinal fluid (CSF) biomarkersMethodIndividuals from the PREVENT‐AD cohort were included in the study. Participants had Aß and tau plasma measurements and at least one year of clinical follow‐up thereafter (n = 278). A subset of participants had CSF measurements (n = 102) and/or PET scans (n = 133) also with 1‐year clinical follow‐up. Participants were cognitively unimpaired at the time of all biomarker measurements. MCI diagnoses were made by clinical consensus among expert clinical and research staff blind to plasma, CSF, PET, MRI and APOE genotype. We established thresholds of plasma and CSF Aß and tau positivity based on >80% specificity in identifying individuals with significant levels of Aß‐PET (plasma Aß42/40 = 0.057; plasma pTau181 = 7.53 pg/mL; CSF Aß42 = 961.37; CSF pTau181 = 66.59 pg/mL). Aß ([18F]NAV4694) and tau ([18F]AV1451)PET thresholds were defined by the mean plus 2 standard deviations from young participants (Aß SUVR cut‐off = 1.17; tau SUVR cut‐off = 1.24).Result36.8% (7/19) of the A+T+ plasma group progressed to MCI, 50% (4/8) of the A+T+ CSF group progressed to MCI, and 46.6% (7/15) A+T+ PET group progressed to MCI (Fig. 1).We found differences in MCI progression status between the A+T+ group compared to the A‐T‐ and A+T‐ groups across all biomarkers’ measurements, with the A+T+ group always showing a higher rate of progression than the other two groups (post‐hoc chi‐square analyses; p<0.05).ConclusionAbnormal levels of Aß and tau plasma biomarkers can help predict near‐ term progression to MCI. When plasma thresholds are derived based on PET data, however, plasma biomarkers have a slightly lower specificity than PET and CSF biomarkers, and both plasma and CSF biomarkers are less sensitive than PET biomarkers.
The cortical glucose metabolism signatures of cognitive resilience in amyloid positive cognitively unimpaired elderly adults
Authors: Liu Lin , Sun Pan , Lan Guoyu , Cai Yue , Li Anqi , Zhu Yalin , Ma Shaohua , Guo Tengfei 
Published: December 2023

AbstractBackgroundß‐amyloid (Aß) positive (A+) cognitively unimpaired (CU) individuals who maintain normal cognitive function at follow‐up may have good cognitive resilience (CR). A+/CU Individuals with high CR may have hypermetabolism. In this study, we explored the cortical glucose metabolism features of CR in A+/CU elderly adults.MethodWe analyzed 855 ADNI participants with Aß PET (18F‐florbetapir (FBP) or 18F‐florbetaben (FBB)), CSF p‐Tau181, 18F‐fluorodeoxyglucose (FDG) PET and longitudinal residual hippocampal volume (rHCV) and cognitive assessments. A+/T+/N+ were defined as AD summary cortical standardized uptake value ratio (SUVR) for FBP = 1.11 or FBB = 1.08, CSF p‐Tau = 23pg/ml, and rHCV = ‐0.67 respectively. We compared intensity‐ and spatial‐normalized FDG SUVR images between 96 A‐/T‐/N‐/CU individuals (Reference group) and 68 A+/CU individuals who maintained CU at follow‐up regardless of T+ or N+ (CR group). Cortical regions with higher FDG SUVR in the CR group were identified as the CR_metaROI. Baseline CR_metaROI FDG‐SUVRs were compared between different stages of AD. Finally, we determined whether CR_metaROI FDG‐SUVR can modulate the association of Aß PET and CSF p‐Tau with longitudinal changes of cognition, controlling for age, sex, and education.ResultCR_metaROI was primarily located in the precentral and postcentral regions (Fig. 1). AD dementia patients had lower CR_metaROI FDG SUVRs than the CU (standardized ß (ßstd) = ‐0.326[95% confidence interval (ci): ‐0.534, ‐0.119], p = 0.002) and MCI (ßstd = ‐0.303[95%ci: ‐0.496, ‐0.111], p = 0.002) groups (Fig. 2A), and A+/CU group had higher (ßstd = 0.605[95%ci: 0.352, 0.859], p<0.001) CR_metaROI FDG SUVRs than the A‐/CU group (Fig. 2B). A‐/T+ and A+/T‐ individuals had lower (ßstd = ‐0.248[95%ci: ‐0.4474, ‐0.022], p = 0.031) and higher (ßstd = 0.305[95%ci: 0.093, 0.516], p = 0.005) CR_metaROI FDG SUVRs than the A‐/T‐ group respectively (Fig. 2C). The A+/T‐/N+ group had higher (ßstd = 0.466[95%ci: 0.153, 0.779], p = 0.004) CR_metaROI FDG SUVRs than the A‐/T‐/N‐group (Fig. 2D). Moreover, higher baseline metaROI FDG‐SUVRs were associated with slower rates of decline in memory, executive function and preclinical Alzheimer cognitive composite scores upon the same levels of Aß PET (Fig. 3A‐C) and CSF p‐Tau (Fig. 3D‐F).ConclusionWe identified a metabolism signature of CR in A+/CU elderly adults. These findings may provide novel insights into understanding the hypermetabolism patterns of CR in aging people.
Middle Age Prevention of Future Alzheimer’s Disease and Related Dementias with Intensive Treatment of Hypertension: Middle PATH Clinical Trial Proposal
Authors: Pruzin Jeremy J. 
Published: December 2023

AbstractStrong epidemiological evidence from multiple studies suggests that elevated systolic blood pressure (SBP) in midlife is a risk factor for Alzheimer’s disease and Related Dementias (ADRD) later in life. The most common neuropathology of biomarker‐confirmed AD is combined AD neuropathological changes and cerebrovascular disease. Hypertension is a leading cause of cerebrovascular disease. The SPRINT MIND trial demonstrated that a goal SBP<120 mm Hg reduced risk for combined mild cognitive impairment (MCI) and dementia by 15% in older individuals compared to a goal SBP<140 mm Hg. SBP can be safely treated with inexpensive medications. Despite being potentially safe and cost‐effective, with strong supporting evidence for benefit, intensive SBP lowering in midlife to reduce future ADRD risk has never been studied, likely because clinical outcomes of MCI and dementia are not practical in this age range in a trial that is usually limited to about 5 years. Elevated SBP is a major risk factor for white matter hyperintensity volume (WMHV) accumulation, an MRI marker with extensive evidence demonstrating this to be associated with and predictive of incident ADRD, making WMHV a suitable surrogate outcome for the initial trial period. While we acknowledge the challenges of using a surrogate outcome, there is no suitable alternative when testing interventions to lower future ADRD risk starting in middle age, a strategy that we believe is essential. The Alzheimer’s Prevention Initiative and Wake Forest have formed a collaboration to investigate the effect of goal SBP<120 mm Hg compared to the SBP achieved by enhanced usual care (SBP = 135 mm Hg) on annualized rate of WMHV accumulation in persons ages 45‐65 who have some existing vascular risk at baseline. Secondary outcomes of changes in AD blood biomarkers and relevant cognitive test scores will help elucidate whether and how SBP and AD are interactive or independent deleterious pathophysiological processes. The intention, should the initial phase prove successful, is to continue and expand the trial until a clinical benefit can definitively be assessed.
Thalamic Contributions to Functional Circuitry in Preclinical Alzheimer’s Disease
Authors: Li Joyce S , Tun Samantha M , Lacadie Cheryl , Fredricks Carolyn 
Published: December 2023

AbstractBackgroundThalamic nuclei are heterogeneously impacted by Alzheimer’s disease (AD) pathology. The anterior thalamus shows tau deposition early on in AD, while other nuclei, such as the mediodorsal (MD) thalamus are spared by tau until much later in the disease process (Braak and Braak, 1991). Furthermore, anterior and MD thalamus have dissociable roles in memory performance – the anterior has a greater role in recollective memory, while the MD plays a role in familiarity. Additionally, the anterior thalamus has direct anatomical links to brain regions implicated in poor short‐term memory performance in AD, while MD thalamus connectivity is primarily to regions spared of AD pathology until late. We sought to identify differences in functional connectivity between the anterior and MD thalamus in amyloid negative and positive individuals.MethodWe examined resting‐state functional MRI data from the A4 study (n = 569), including 254 healthy controls and 315 individuals with preclinical AD based on amyloid SUVR>1.14 (Table 1). We assessed functional connectivity of anterior and MD thalamus to the whole brain using 2mm radius spherical seeds at the center of mass of Morel atlas nuclei. All results were covaried for age, sex, handedness, and years of education.ResultAnterior thalamic activity was positively correlated with parahippocampal gyrus, fusiform, and insula, and negatively with the striatum and thalamus. MD thalamic activity was positively correlated with the amygdala, ventral striatum, and anterior cingulate, and negatively correlated to the superior temporal gyrus and regions of the parieto‐occipital lobe. In preclinical AD, compared with HCs, the positive correlations in either thalamic nuclei were lost.ConclusionThe thalamic functional connectivity observed agrees with preexisting literature dissociating structures related to the anterior and MD thalamus. Our results provide a basis for further exploration of thalamic nuclei to AD‐involved functional networks, as well as future analysis of the observed connectivity measures to cognition.
Blood transcriptomics differentiate tau positive discordant and concordant individuals
Authors: Souza Lara Angi , Schlickmann Thomas , Machado Luiza Santos , Pascoal Tharick A. , De Bastiani Marco Antônio , Zimmer Eduardo R 
Published: December 2023

AbstractBackgroundLevels of soluble hyperphosphorylated tau (p‐tau) in the cerebrospinal fluid (CSF) and tau tangles measured by positron emission tomography (PET) are used to determine tau positivity in Alzheimer’s disease (AD). However, a mismatch between CSF and PET positivity occurs in some cases. In fact, it is thought that CSF tau biomarker abnormalities may precede changes in tau‐PET imaging. With this in mind, the aim of our study was to examine the blood transcriptomic phenotypes in individuals presenting tau positivity biomarker discordance.MethodBlood transcriptomics data from 64 individuals (cognitively unimpaired = 31 and cognitively impaired = 33) were obtained from the ADNI database. We divided these individuals into negative (CSF‐PET‐), discordant (CSF‐PET+ and CSF+PET‐) and positive group (CSF+PET+) to tau biomarkers. We also performed differential expression analyses (DEA) using the limma package. Additionally, we conducted a KEGG pathway enrichment analysis using altered genes obtained from DEA (p‐value < 0.05). Amyloid B42, total tau, Mini Mental State Examination, Clinical Dementia Rating Sum of Boxes, APOE4 status, education, and gender difference in the groups were described in Fig1. Data were analyzed with Pearson’s Chi‐squared test and Linear Model ANOVA. All statistical analyses were performed in R.ResultOur analysis revealed that discordant and positive individuals had, respectively, 1191 and 314 DEGs if compared to negative individuals. Interestingly, we found 324 DEGs in common between them (Fig2A‐C). In the KEGG functional enrichment analysis (Fig3), we observed that the main terms were enriched in the tau discordant individuals were related to aminoacids metabolism and inflammation (Fig3A). In the CSF+/PET+ individuals pathways related to calcium signaling and viral response were the most altered compared to CSF‐/PET‐ (Fig3B).ConclusionOur results indicate that blood transcriptome differs among tau negative, discordant and positive individuals. This suggests that multiple biological pathways in the blood are dependent on tau changes. Further investigation of DEGs clusters possibly could demonstrate new insights about tau mechanisms involved in the disease.
Antemortem MRI detects atrophy related to hippocampal sclerosis pathology in the oldest‐old but side matters: The 90+ Study
Authors: Woodworth Davis C. , Li Janice X. , Faramarzi Sina , Greenia Dana E. , Bukhari Syed A. , Montine Thomas J. , Kawas Claudia H. , Corrada María M. M. , Sajjadi S. Ahmad 
Published: December 2023

AbstractBackgroundHippocampal sclerosis of aging (HS) is the neuropathological finding of neuronal death and gliosis in the hippocampus. HS is more prevalent, and associated with dementia, in the oldest‐old (those = 90 years), but cannot be diagnosed during life. HS is often unilateral and can be missed if only one brain hemisphere is assessed, which is standard neuropathological practice but may hamper the development of biomarkers for HS. Here we examined hippocampal volumes from antemortem MRI in relation to bilaterally‐assessed HS at autopsy, accounting for side, in oldest‐old participants from The 90+ Study.MethodWe included participants with both autopsy and antemortem MRI data. All participants had neuropathological assessment of HS for both hemispheres. We performed hippocampal segmentation of antemortem 3D‐T1w MRIs using FreeSurfer, adjusting by intracranial volume. We compared total average (average of left and right), left, and right, hippocampal volumes between those with and those without HS. For HS participants we combined the hippocampal volumes from each hemisphere with HS into a single group and from each hemisphere without HS into a separate group, and compared these to the average hippocampal volumes from those without HS. We used Welch’s T‐tests for comparisons and report Cohen’s d effect sizes.ResultParticipant characteristics (N = 89) are shown in Table‐1. All HS was unilateral (Right = 6, Left = 4). Average total hippocampal volume was not significantly different between those with and those without HS (d = 0.51, P = 0.11, Figure‐1a). However, right hippocampal volumes were significantly related to right‐sided HS with a large effect size (P = 0.002, d = 1.02) and left hippocampal volumes had a large effect size for left‐sided HS (P = 0.17, d = 0.90, Figure‐1c), whereas this was not the case when HS was on the opposite side (P>0.3, d<0.4, Figure‐1b,c). Combined HS participant hippocampal volumes for the side with HS (d = 0.98, P = 0.003), but not the side without HS (d = ‐0.14, P = 0.7), were different from volumes in participants without HS (Figure‐1d).ConclusionOur results suggest HS is detectable by atrophy on antemortem MRI, but most strongly when using hippocampal volumes from the same side as HS. Researchers should consider assessing and documenting the presence of HS in both hemispheres to accelerate development of neuroimaging biomarkers for HS.
Computational progression subtypes of hypometabolism due to Alzheimer’s disease: towards linking antemortem and postmortem diagnoses
Authors: Oxtoby Neil P , Shand Cameron , Bourgeat Pierrick 
Published: December 2023

AbstractBackgroundPostmortem diagnosis of Alzheimer’s and related pathologies remains the gold standard. Advanced neuroimaging techniques enable assessment of some pathologies in living subjects, but antemortem signatures are often defined post hoc in postmortem‐defined groups. Here we flip this and estimate data‐driven antemortem signatures of pathology using Subtype and Stage Inference (SuStaIn), then predict postmortem classification. SuStaIn is a machine learning algorithm that jointly estimates subtype clusters of data‐driven disease progression signatures to uniquely unravel spatiotemporal heterogeneity using cross‐sectional neuroimaging data. We evaluate SuStaIn on FDG‐PET scans to produce the first AD subtypes of hypometabolism and explore links with LATE‐NC.MethodADNI data was downloaded 06/2022. Model inputs were baseline FDG‐PET SUVR (Desikan‐Killiany parcellation) extracted using FreeSurfer from the N = 1181 (286/791/104 AD/MCI/Ab+CN) available ADNI participants having both T1w MRI and FDG‐PET at baseline. Biomarkers were converted into w‐scores relative to 203 controls (Ab–CN), adjusted for control trends in age and sex using robust linear regression. Postmortem diagnoses (N = 43) of AD/LATE‐NC/mixed were predicted. Modeling: Hypometabolism subtypes were estimated using SuStaIn. A bespoke “disease signal” approach selected informative biomarkers for w‐score events of interest: 1 (mild), 1.5 (moderate), 3 (severe). Average out‐of‐sample log likelihood (10‐fold cross‐validation) selected the final model (#subtypes, max 5). Statistical Analysis: Subtype group comparisons of cross‐sectional outcomes and postmortem pathology were performed using common statistical tests.ResultFigure 1 shows the four subtypes of hypometabolism resulting from our analysis: Typical (limbic+temporal, N = 283: 21/190/72 CN/MCI/AD), Limbic Sparing (N = 261: 19/157/85), Aggressive Typical (early high w‐scores; N = 90: 2/40/48), and Lateral Cortical (N = 62: 1/33/28), with N = 485 (41%) not subtyped. Cognition was worse in the Aggressive Typical/Lateral Cortical subtypes than the Typical/Limbic Sparing (MMSE 25 vs 27; ADAS‐Cog13 19 vs 27) Kruskal‐Wallis test p<10‐3. Figure 2 shows subtyping and staging results (59% subtypeable: N = 696), with AD cases distributed evenly within each subtype and MCI at earlier stages, as expected. Figure 3 is a confusion matrix showing that our model imperfectly predicted postmortem LATE‐NC diagnosis.ConclusionData‐driven antemortem spatiotemporal subtypes of hypometabolism in Alzheimer’s disease were imperfectly predictive of postmortem LATE‐NC/AD classification in a small sample. Validation on larger histopathology samples is necessary to make general conclusions.
Longitudinal morphometry of medial temporal lobe subregions in earlyAlzheimer’s disease
Authors: Baumeister Hannah , Gellersen Helena M , Kleineidam Luca , Wolfsgruber Steffen , Bürger Katharina , Laske Christoph , Perneczky Robert , Peters Oliver , Priller Josef , Schneider Anja , Spottke Annika , Teipel Stefan , Wiltfang Jens , Heneka Michael T. , Düzel Emrah , Jessen Frank , Berron David 
Published: December 2023

AbstractBackgroundStructural MRI is frequently used to track Alzheimer’s disease (AD) progression in clinic, research, and pharmacological trials. It has been shown that established MRI‐derived measures lack diagnostic sensitivity particularly in early stages of AD. Here, we investigate if the utility of structural MRI for tracking early AD progression can be increased when focusing on subregions of the medial temporal lobe (MTL) which are known to exhibit earliest AD‐related neuropathological change.MethodWe used data from N = 143 participants enrolled in the DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE). This included cognitively unimpaired participants who were either Aß‐negative (CU Aß‐; n = 67) or Aß‐positive (CU Aß+; n = 20), Aß+ participants with subjective cognitive decline (SCD Aß+; n = 38), and Aß+ participants with MCI (MCI Aß+; n = 18). Participants underwent annual assessments up to three years after baseline, including MRI (2.19 ± 0.86 follow‐ups) and a neuropsychological testing (2.18 ± 0.83 follow‐ups). Segmentations of MTL subregions were generated using a longiudinal, template‐based implementation of the Automated Segmentation of Hippocampal Subfields (ASHS; Yushkevich et al., 2015, Hum Brain Mapp.) algorithm (Figure 1). Linear mixed models were fitted to derive volumetric slopes and to test their relationship with longitudinal changes in Preclinical Alzheimer Cognitive Composite (PACC‐5) scores.ResultWe observed significant volume losses across diagnostic groups with the MCI Aß+ group exhibiting the fastest rates. Compared with the CU Aß‐ group, there were accelerated volume losses in the subiculum and dentate gyrus in the SCD Aß+ group and, additionally, in the entorhinal cortex and Brodmann areas 35 and 36 in the MCI Aß+ group. There was also a trend towards faster volume losses in the entorhinal cortex in the CU Aß+ group. Higher rates of MTL subregional volume losses, particularly in the cornu ammonis 1 subfield, were related to a faster decline on the PACC‐5 in the MCI Aß+ group. This effect remained significant when controlling for baseline volumes.ConclusionOur findings highlight the viability of subregional MTL morphometry for tracking earliest neurodegeneration and related cognitive decline due to AD.