bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporal lobe function during memory encoding in older individuals prior to the onset of cognitive impairment
Authors: Beason‐Held Lori L , Shafer Andrea T , Calcagno Nicole , Kitner‐Triolo Melissa , Resnick Susan M. 
Published: December 2023

AbstractBackgroundPrevious studies have shown that resting state brain function begins to change in the years leading up to the development of cognitive impairment. This study examines temporal lobe function during memory encoding approximately 2.5 years before the onset of cognitive impairment in Baltimore Longitudinal Study of Aging (BLSA) participants.MethodBLSA participants with subsequent memory impairment (Subsequently Impaired (SI), n = 22, mean age = 83.6, time to impairment = 2.5 ± 1.1 SD years post‐scan) and age, sex, and education matched cognitively normal participants (Cognitively Normal (CN), n = 64, mean age = 84.9) performed a face‐scene encoding task during fMRI scanning. Group differences in task performance and brain activation patterns were examined during encoding trials they later remembered, and trials they later forgot during the recognition phase of the task.ResultThe SI group performed more poorly than the CN group during the recognition phase of the task. Both CN and SI activated the occipitotemporal visual pathway during memory encoding. Yet relative to CN participants, the SI group showed decreased activation of the hippocampus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus during encoding of face‐scene pairs. This decreased activation was seen during both encoding of pairs they later remembered and pairs they forgot during recognition.ConclusionBoth memory dysfunction and decreased temporal lobe activity during encoding begin before the onset of clinically evident cognitive impairment. In the SI group, the decreased temporal lobe activation was seen regardless of whether they later remembered or forgot the face‐scene pairs during the recognition task. This suggests that those who go on to develop impairment have an overall weaker functional response in temporal lobe regions during memory encoding. Further examination of the functional connectivity of these regions may help to determine if differences in brain network characteristics are related to subsequently remembered or forgotten visual stimuli during encoding. This work was supported by the Intramural Research Program of the NIH, National Institute on Aging.
Plasma biomarkers across the spectrum of Alzheimer’s and Parkinson’s disease: Association with cortical thickness and cognitive dysfunction
Authors: Coughlan Gillian T , Zhukovsky Peter , Sanchez Erlan , Grady Cheryl , Munoz Douglas , Black Sandra E. , Buckley Rachel F. , Masellis Mario 
Published: December 2023

AbstractBackgroundPlasma biomarkers of phosphorylated‐tau(p‐tau), astrocytosis and axonal damage offer a reliable means of identifying and measuring multiple pathological processes in‐vivo. How these biomarkers are associated with cortical brain structure and cognition within, and across, disorders is unclear. Leveraging the Ontario Neurodegenerative Disease Research Initiative, we examined the cross‐sectional association between plasma biomarkers, cortical thickness, and multi‐domain cognition.Method290 participants diagnosed with AD or PD (in accordance with clinical guidelines) and healthy controls (HC) were included (MeanAge = 68.96;[41% women; 35% APOE4carriers]). Four groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 121), ii)PD with MCI or dementia(PDMCI/PDD;N = 78), iii)PD with normal cognition(PD‐NC;N = 43) and HC(N = 44; Table1). Plasma measures of p‐tau181‐UGOT, Neurofilament light chain (NfL) and GFAP, alongside FreeSurfer‐derived cortical thickness were included. A neuropsychological battery was administered. All models were adjusted for age, sex, and education.ResultThere was an effect of diagnostic group on global cortical thickness, with PD‐NC, ADMCI/ADD and PDMCI/ADD exhibiting a significant reduction relative to HC(Fig1A). Regional patterns of brain atrophy were significantly associated in ADMCI/ADD and PDMCI/ADD(Fig1B). Across groups, p‐tau181, GFAP and to a lesser extent NfL, were associated with cortical thinning, particularly in lateral temporal and medial parietal regions (Fig2A). Unlike global thickness, ADMCI/ADD and PDMCI/PDD, but not PD‐NC, showed reduced thickness in the regions associated with p‐tau181, GFAP and NfL (Fig2B). Diagnostic group*GFAP/NfL/ptau181 interactions were not significant. Mediation analysis showed the cortical thinning in lateral temporal and medial parietal regions mediated between 33% to 40% of association between p‐tau181 and delayed memory. Similarly, thinning in these areas mediated 22% to 33% of the relationship between GFAP and executive function(Fig2C).ConclusionWe conclude that there is a similar pattern of gray matter loss in MCI/Dementia due to AD and PD. Higher concentrations of plasma p‐tau181 and GFAP are associated with poorer memory and executive function, in part through cortical thinning in lateral temporal and medial parietal regions. In conclusion, pathological processes related to the deposition of amyloid and tau, as well as astrogliosis, may co‐exist across cognitively impaired individuals with AD and PD. This is consistent with autopsy findings showing that AD pathology is present in 33‐60% of PD patients.
An exploratory pilot study on diffusion MRI measurement of cortical microstructural neurodegeneration for the assessment of dementia in a Japanese hospital setting
Authors: Ridgway Gerard R , Nakajima Takashi , Torso Mario , Valotti Michele , Hardingham Ian , Ehsan Omar , Chance Steven A 
Published: December 2023

AbstractBackgroundThe use of diffusion MRI (dMRI) to assess cortical microstructure has demonstrated promise for measuring neurodegeneration in Alzheimer’s disease (PMID:33174658, PMID:36281682) and frontotemporal dementia (PMID:32641807, PMID:34686217) using retrospective research datasets. The ultimate translation of research findings to clinical practice requires prospective studies in hospital settings. A pilot study at the National Hospital Organization, Niigata, was designed and successfully delivered.MethodThe study was registered on Oct 5th 2021 (jRCT1032210367). Scanning took place between Oct 13th 2021 and June 30th 2022, on a 1.5T Philips Ingenia. MRI data was transferred using a secure cloud gateway (Cimar). A total of 10 healthy controls (HC), 10 Alzheimer’s disease (AD) patients, and 5 frontotemporal dementia (FTD) patients were recruited. Structural (3D T1‐weighted) and dMRI (2mm isotropic, 32 directions at b = 1000 s/mm2) scans were used to calculate cortical mean diffusivity and three neuropathologically‐inspired cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+). Metrics were also summarized over AD signature regions (Ridgway et al., CTAD 2022).ResultOf the n = 25 cases, 18 had clear clinical diagnoses after neurological and radiological assessment, while 7 were more complex (including focal bleeding, focal ischemia, meningioma, supra‐sellar tumour). Characteristics are given in Table 1. Figure 1 plots two whole‐brain measures: PerpPD+ and AngleR. A threshold of PerpPD+ > 1.325 has 100% sensitivity to the 8 clear AD cases, with 86% specificity for 7 controls vs AD. Results were less clear for FTD using whole‐brain measures alone. The Cohen’s d effect size for clear AD versus clear HC was 2.82 using whole‐brain PerpPD+. Using signature regions (Figure 2b) improved separation to d = 3.08 for PerpPD+, compared to d = 1.87 for the cortical thickness signature (Figure 2a).ConclusionThe pilot study demonstrated practical feasibility and good performance for distinguishing AD from HC using cortical diffusivity measures acquired at the 1.5T field‐strength common in hospitals in Japan. Future work will investigate FTD signature regions. A larger multicentre study assessing diagnostic accuracy using additional AD biomarkers is warranted.
MK‐6240 tau‐PET in an Aβ‐enriched sample from the 1946 British birth cohort
Authors: Coath William , Markiewicz Pawel J , Modat Marc , Scott Catherine J , Malone Ian B , Arstad Erik , Awais Ramla , Sander Kerstin , Weston Philip SJ , Thomas David L , Dickson John , Schöll Michael , Ourselin Sebastien , Richards Marcus , Fox Nick C , Cash David M , Schott Jonathan M 
Published: December 2023

AbstractBackgroundWe investigated imaging biomarkers of Aß and neurodegeneration in relation to tau‐PET Braak stage in a preclinical birth cohort.MethodCognitively normal individuals enrolled in Insight 46, the neuroimaging sub‐study of the MRC National Survey of Health and Development (1946 British birth cohort), were scanned on combined PET/MR with [18F]florbetapir Aß‐PET at age ∼70 years and again at ∼73 years. A sub‐sample enriched for Aß (Aß+; Centiloid> = 13, hole cerebellum reference) is currently being assessed with [18F]MK‐6240 tau‐PET at age ∼76 years. For this interim analysis, tau‐PET images (90‐110 minutes post‐injection) were co‐registered with T1‐weighted MRI. Anatomical areas were parcellated on the T1 to form Braak regions. Standard uptake value ratios (SUVRs) were calculated using an inferior cerebellar grey reference without partial volume correction. Tau‐PET positivity (Tau+) was defined using Gaussian mixture modelling in each region. Participants were assigned to Tau‐, Braak I‐II, III‐IV or V‐VI groups based on the most advanced Tau+ region. Group differences in baseline Aß (Centiloids), Aß accumulation (Centiloids/year) and hippocampal atrophy rate (%/year) were investigated with Mann‐Whitney U tests.ResultAnalysis included 80 individuals with tau‐PET data (Table 1), 45% of the sample were Aß+ by age 73. Three individuals did not conform to the Braak stage hierarchy (orange triangles, Figure 1). No Aß‐ individuals were Tau+ beyond Braak I. Figure 2 shows baseline Aß, Aß accumulation and hippocampal atrophy rates for Braak stage groups for participants who had data at all timepoints (N = 78). Tau+ individuals (in any Braak region) had significantly higher baseline Aß than Tau‐ individuals. Rate of annual Aß accumulation was higher for Braak III‐IV and Braak V‐VI compared to Tau‐ individuals. Hippocampal atrophy rate was elevated for Braak V‐VI compared to Tau‐, and Braak III‐IV was borderline significant.ConclusionIn this preliminary analysis, tau‐PET positivity beyond Braak I was restricted to individuals who were Aß+ three years prior. Participants with elevated tau aged 76 had increased Aß at age 70. Increased rates of hippocampal atrophy were occurring at least three years prior to tau scanning in individuals with advanced tau pathology. These findings will be updated as more data is acquired.
Lineage and geometry of MRI‐visible perivenous and periarterial spaces in white matter confirmed on immunohistochemical microscopy
Authors: Schwartz Daniel , Roese Natalie E , Hurworth Justin , Lahna David , Wall Rachel C , Kaye Jeffrey A , Woltjer Randy L , Silbert Lisa C 
Published: December 2023

AbstractBackgroundMRI‐visible perivascular spaces (mrPVS) in the brain, typically found in white matter and assumed to be pathologically enlarged though historically considered a benign finding, have been more recently associated with normal aging as well as with various disease states, including traumatic brain injury, sleep apnea, Alzheimer’s Disease (AD), Parkinson’s Disease, and cerebral amyloid angiopathy. One putative cause for their pathological enlargement has been damage to the parenchyma surrounding the PVS, bounded by the astrocytic endfoot, caused by an increase in vascular pressure or pulsatility. Arteries are more pulsatile than veins, and thus it is expected that mrPVS, presumed to be enlarged, will be predominately around arteries. This pre and post mortem MRI + immunohistochemistry (IHC) study sought to clarify the lineage and spatial distribution of PVS visible at the resolution of MRI in aged individuals who were cognitively normal (C), mildly cognitively impaired (MCI), had clinical signs of dementia and mixed AD and vascular disease at pathology (AD/VD), and had pathology‐confirmed AD only (AD).MethodDetailed imaging and IHC acquisition, as well as MRI and IHC processing and registration methods, can be found at [https://pubmed.ncbi.nlm.nih.gov/36343095/ and https://pubmed.ncbi.nlm.nih.gov/36054513/]. Each MRI was inspected for PVS by an experienced rater (JH) and trichrome and smooth muscle actin (SMA) IHC of the corresponding vessels were judged to be arteries or veins based on SMA positivity and morphology (DLS).Result35 mrPVS over 19 subjects’ post mortem MRIs were unequivocally identified on trichrome and SMA. Of these, 23 surrounded arteries (SMA+, Fig. 1), and 12 surrounded veins (faint/thin/uneven SMA, Fig. 2). Mean distance (range) to the cortical ribbon from mrPVS surrounding arteries and veins were 2.8mm[0‐8mm] and 5.4mm[2‐14mm], respectively.ConclusionPVS large enough to be visible on MRI are more frequently arterial if nearer the cortical ribbon; mrPVS nearer the ventricle are more likely to be collecting veins. As collecting veins nearer the ventricles and arterioles in cortex tend to have higher pulse pressures, this finding is congruent with the hypothesis that PVS may enlarge as a result of higher vascular pressures common in older age and cerebrovascular disease.
Longitudinal trajectories of myelin loss in the context of Alzhiemer’s disease biomarkers, glial activation, and APOE4
Authors: Stephenson Henry G. , Kohli Akshay , Kecskemeti Steven R , Rubinski Anna , Ewers Michael , Alexander Andrew L , Deming Yuetiva , Ma Yue , Van Hulle Carol A. , Langhough Rebecca E , Jonaitis Erin M. , III Douglas C Dean , Ulland Tyler K. , Chin Nathaniel A. , Okonkwo Ozioma , Betthauser Tobey J , Asthana Sanjay , Kollmorgen Gwendlyn , Carboni Margherita , Wild Norbert , Carlsson Cynthia M , Johnson Sterling C , Blennow Kaj , Zetterberg Henrik , Bendlin Barbara B 
Published: December 2023

AbstractBackgroundLower measures of myelin have been associated with abnormal levels of AD biomarkers and APOE4 carriage. However, most human studies have been cross‐sectional, leaving the relationship between AD and myelin changes unclear. The purpose of this study was to determine the association between AD pathology, APOE4, glial activation, and longitudinal changes in quantitative R1 (qR1), a marker sensitive to myelination obtained via MPnRAGE MRI.MethodParticipants from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and Wisconsin Alzheimer’s Disease Research Center (ADRC) were selected based on available longitudinal MPnRAGE, clinical diagnosis, and APOE genotyping (N = 446). A subset (N = 141) included those with available baseline CSF (AB42/40, pTau181), and gliosis markers (sTREM2, GFAP, YKL40) measured using a robust prototype assay as part of the Roche NeuroToolKit research platform (Roche International). Longitudinal mean qR1 was estimated from white matter regions from the ICBM‐DTI‐81 atlas. In the overall sample, linear mixed effects models predicting regional qR1 (FDR‐corrected) with random intercepts and slopes were estimated controlling for sex, age centered within‐subjects (agec), age averaged within‐subjects (agegm), cognitive impairment, and APOE4 carriage as covariates. Two‐way interactions between impairment and APOE4 with agec were tested in the overall sample as were moderating effects of CSF amyloid‐positivity, pTau181, and gliosis markers on agec in the CSF sample.ResultIn the overall sample, older agec, agegm, and female sex were associated with lower qR1 in a majority of tracts indicating substantial longitudinal declines in qR1 over time and lower qR1 with advanced age and female sex. Sex, impairment, and APOE4 did not show significant agec interactions. Likewise, none of the CSF biomarkers moderated the effect of agec in the CSF subsample.ConclusionWhile aging is robustly associated with longitudinal demyelination as potentially indexed by qR1, these rates do not appear to be moderated by AD pathology, cognitive impairment, APOE4, or glial activation in early disease. Given the capacity for re‐myelination in the context of injury, longitudinal studies are critical for parsing myelin and AD relationships. Established associations between myelin and AD risk may reflect later disease processes, particularly in samples more enriched for tau pathology.
Effects of biomarker timing on preclinical cognitive trajectories and tau PET accumulation
Authors: Cody Karly Alex , Langhough Rebecca E , Janelidze Shorena , Christian Bradley T. , Johnson Sterling C , Hansson Oskar , Betthauser Tobey J 
Published: December 2023

AbstractBackgroundThe timing of AD biomarker positivity may be important for defining optimal anti‐amyloid therapy windows for secondary prevention. This work characterizes the AD biological cascade and investigates biomarker onset timing and associations of timing with preclinical cognitive decline and tau PET accumulation using data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP).MethodWRAP participants (N = 172; mean(SD) age at last plasma = 69.4(6.6) years; 159 unimpaired, 9 MCI, 3 dementia, 1 impaired non‐AD) with available plasma pTau217, amyloid PET, and longitudinal cognitive assessments were included. Plasma pTau217 was quantified using an immunoassay on the Meso Scale Discovery platform (Lilly Research Laboratories). Amyloid burden was quantified using cortical 11C‐PiB DVR (cerebellum GM reference region). Positivity thresholds were defined using group‐based trajectory modeling applied to participants with longitudinal (≥2) biomarker observations (Ptau217, n = 162; PiB, n = 155). Sampled iterative local approximation (SILA) was used to model longitudinal PiB and pTau217 trajectories and estimate biomarker onset ages. Biomarker timing groups were defined as: PiB(‐)/pTau217(‐); coincident (PiB(+) and pTau217(+) onsets within 2 years of each other); PiB(+) first; or pTau217(+) first. We used a linear mixed effects model (random intercept and age‐related slope; unstructured covariance) to investigate the impact of biomarker timing group on cognitive decline measured by a three‐test Preclinical Alzheimer’s Cognitive Composite (PACC‐3). In a subset with tau PET (n = 120), we assessed regional tau burden (18F‐MK‐6240 SUVRs; 70‐90min, inferior cerebellar GM reference region) relative to plasma pTau217(+) and PiB(+) timing.ResultIn the PiB(+)/pTau217(+) subset (n = 60; 35%), PiB(+) onset generally preceded pTau217(+), but with considerable heterogeneity in this timing (Figure 1A‐H). Older age at PiB(+) onset was associated with shorter time to pTau217(+) onset (Figure 1G‐H). In PACC‐3 analyses, post‐hoc analyses of the significant biomarker timing group*age interaction showed fastest decline in the pTau217(+) first group (Figure 2). Both PiB(+) and pTau217(+) durations predicted MK‐6240 accumulation; ∆AICc indicated better fit with pTau217(+) time (Figure 3).ConclusionIn this mostly preclinical sample, the timing of PiB(+) and plasma pTau217(+) were differentially associated with cognitive decline and tau PET accumulation. These preliminary findings suggest secondary AD prevention with anti‐amyloid therapy may be most beneficial before pTau217 onset.
Plasma biomarkers of Alzheimer´s disease in the continuum of dementia with Lewy bodies
Authors: Diaz‐Galvan Patricia , Przybelski Scott A. , Algeciras‐Schimnich Alicia , Lesnick Timothy G. , Schwarz Christopher G. , Senjem Matthew L. , Gunter Jeffrey L. , Jack Clifford R. , Min Paul H , Jain Manoj K. , Miyagawa Toji , Forsberg Leah K. , Fields Julie A. , Savica Rodolfo , Graff‐Radford Jonathan , Ramanan Vijay K , Jones David T. , Botha Hugo , St Louis Erik K , Knopman David S. , Graff‐Radford Neill R , Ferman Tanis J , Petersen Ronald C. , Lowe Val J. , Boeve Brad F. , Kantarci Kejal 
Published: December 2023

AbstractBackgroundPatients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aß), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.MethodWe included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aß40, Aß42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aß40/42. Lower Aß40/42 indicates increased Aß pathology. Plasma Aß40, Aß42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aß and 18F‐Flortaucipir for tau.ResultHigher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p<0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p<0.001) and NfL (p<0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p<0.001). After accounting for age, plasma Aß40/42 did not correlate with amyloid or tau PET SUVr.ConclusionIn the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.