bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetics to MRI‐DTI: HFE mutation delays AD white matter degeneration in ApoE4 carriers
Authors: Pang Ran , Wang Jianli , Karunanayaka Prasanna , Kanekar Sangam , Beselia Gela , Kaneka Samika , Connor James R , Yang Qing 
Published: December 2023

AbstractBackgroundThe HFE gene involves iron metabolism that directly participates in white matter (WM) myelination process. ApoE4 are known to affect normal myelination through disruptions of iron and lipid metabolism in AD. Thus, we investigated the effect of HFE SNP concurred with the ApoE4 gene mutation in AD WM degeneration. Associations of a neuronal inflammation marker, CSF sTREM2, with DTI measures and cognitive decline were explored for a mechanism under the context of iron metabolism in AD WM degeneration.MethodWhite matter degeneration of ApoE4 carriers with and without HFEH63D polymorphism was investigated using DTI from ADNI database.1 Soluble TREM2 (sTREM2) and pathological protein concentrations in CSF were measured for each CN and AD patients with and without HFE SNP concurred with the ApoE4 gene mutation.ResultMean diffusivity and radial diffusivity of DTI demonstrated an extensive and precipitous age‐related WM degeneration in ADWT/ApoE4+ carriers (as shown in Figure1). This WM degeneration was significantly attenuated in the ADH63D/ApoE4+ subjects with lessened cognitive decline (as shown in Table1, Figure1). The decreased CDR‐cognitive impairment in AD subjects was negatively associated with sTREM2 and positively associated with RD of bilateral inferior longitudinal fasciculus and PTAU (as shown in Table2).ConclusionThe attenuation of WM degeneration and cognitive decline by HFEH63D in AD ApoE4 carriers during aging may involve an effect of reducing neuroinflammation during aging, consistent with reports that HFEH63D establishes a neuroprotective milieu2 and attenuates AD WM neurodegeneration.3 Our in‐vivo data establish a link between interactions of genetic mutation of ApoE with HFE and AD WM degeneration during aging. Reference: • Meadowcroft MD, Wang J, Purnell CJ, et al. Reduced Cerebral White Matter Integrity Assessed by DTI in Cognitively Normal H63D‐HFE Polymorphism Carriers. J Neuroimaging. 2018;28:126‐133. • Wang L, Johnson EE, Shi HN, Walker WA, Wessling‐Resnick M, Cherayil BJ. Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. J Immunol. 2008;181:2723‐2731. • Urrutia PJ, Hirsch EC, González‐Billault C, Núñez MT. Hepcidin attenuates amyloid beta‐induced inflammatory and pro‐oxidant responses in astrocytes and microglia. J Neurochem. 2017; 142:140‐152.
Assessing a universal neocortical mask for Centiloid quantification
Authors: Bourgeat Pierrick , Dore Vincent , Rowe Christopher C , Benzinger Tammie L.S. , Tosun Duygu , Goyal Manu S. , LaMontagne Pamela J. , Jin Liang , Weiner Michael S. W. , Morris John C , Masters Colin L , Fripp Jurgen , Villemagne Victor L 
Published: December 2023

AbstractBackgroundThe Centiloid (CL) project was developed to harmonise the quantification of Aß‐PET scans to a unified scale. The CL neocortical mask was defined using 11C‐PiB, overlooking potential differences in regional distribution among Aß tracers. We created a universal mask using an independent dataset of 5 Aß tracers, and investigated its impact on inter‐tracer agreement, tracer variability and group separation.MethodUsing data from the ADOPIC study (AIBL, ADNI and OASIS3), age‐matched pairs of mild Alzheimer’s disease (AD) (MMSE = 20‐24;CL>25) and healthy controls (MMSE> = 28;CDR = 0;CL<15) were selected: 18F‐Florbetapir (FBP:147 pairs), 18F ‐Florbetaben (FBB:22 pairs), 18F ‐Flutemetamol (FLT:10 pairs), 18F ‐NAV (NAV:42 pairs), 11C‐PiB (PIB:63 pairs). The PET images were smoothed to a uniform 8mm resolution to reduce the influence of different scanner sharpness on the derived masks. The images were then spatially normalised using the SPM CL pipeline and transformed into SUVR (whole cerebellum). For each tracer, the mean AD‐HC difference image was computed and mirrored. The threshold for each difference image was optimised to maximise the overlap with the standard CL mask. The Universal mask was defined as the intersection of all 5 masks. It was then used to recalibrate each tracer into Centiloids. The Universal mask and associated transforms were evaluated on the GAAIN head‐to‐head calibration datasets in terms of inter‐tracer agreement and variance in the young controls (YC). They were also evaluated on the baseline ADOPIC dataset (N = 3565) with the effect‐size between HC/AD and HC/MCI.ResultThe overlap between each tracer specific mask was high (mean Dice = 0.82). The Universal mask was 26% smaller than the Standard one, but the overlap was high (Dice = 0.74). The Universal mask led to a small reduction in the variance of the YC in most tracers (‐3.4%) and a small increase in the R2 between each of the 11C‐PiB/18F‐tracer pairs (+0.24%). In ADOPIC, it led to a higher effect‐size between HC/AD (1.43 vs 1.42) and HC/MCI (0.71 vs 0.70).ConclusionThe universal CL mask led to an increase in inter‐tracer agreement and group separation. Those increases were however relatively small indicating that the existing standard CL mask is suitable for the quantification of all Aß tracers.
Investigating the impact of APOE4 genotype on the association between cerebral blood flow and haematological properties in mid‐life adults
Authors: Dounavi Maria‐Eleni , Mak Elijah , Low Audrey , Williams Guy B , Wells Katie , Muniz‐Terrera Graciela , Lawlor Brian A , Naci Lorina , Malhotra Paresh A , Koychev Ivan , Ritchie Karen , Su Li , Ritchie Craig W , O'Brien John T 
Published: December 2023

AbstractBackgroundCarriership of the apolipoprotein ε4 (APOE4) allele confers a heightened risk for the development of Alzheimer’s disease (AD). Cerebral blood flow (CBF) is decreased in prodromal and established AD, however findings in the preclinical stage are mixed, with some studies reporting increases. CBF can be impacted by many factors including the haematocrit. We investigated in a cohort at risk of developing AD how haematological variables relate to CBF and if this relationship is differentially moderated by APOE4.Method375 participants from the PREVENT‐Dementia study underwent arterial spin labelling (ASL) and structural 3Tesla MRI. ASL data were analysed using BASIL/FSL and structural scans with SPM12. CBF maps were corrected for partial volume effects. A vascular territory mask with nine territories, the middle, proximal and distal branches of the anterior, middle and posterior cerebral arteries (ACA, MCA, PCA) was used for region‐of‐interest analysis and registered to the native ASL space. Regional gray matter (GM) CBF values were harmonised using COMBAT. Linear regression was used to examine differences between APOE4 carriers and non‐carriers controlling for age, sex and years of education. Associations between haematological properties and CBF were examined with Pearson’s correlations. Differential relationships between CBF, haematocrit, and measures of red blood cell size and shape (distribution width (RDW) and mean corpuscular volume (MCV)) were investigated by including interaction terms of APOE4 and haematological variables in the models.ResultAPOE4 carriers had significantly higher CBF in the proximal MCA (t = 2.54, p = 0.01). Across all subjects, RDW and MCV were not associated with GM CBF, though several significant interactions were observed between APOE4 and RDW in predicting CBF (Figure 1). Haematocrit was associated with GM CBF (ρ = ‐0.19, p < 0.01). No significant interactions were seen between APOE4 and haematocrit or MCV in predicting CBF.ConclusionThe variability of the size and shapes of erythrocytes was differentially associated with CBF between APOE4 carriers and non‐carriers suggesting a different response to morphological erythrocyte alterations. This could further relate to underlying factors such as inflammation, which is associated with a higher RDW. Such associations should be examined in further studies.
NODDI May Be More Sensitive to Neurodegenerative Changes Than Structural MRI
Authors: Yu Xi , Gebre Robel K , Przybelski Scott A. , Reid Robert I. , Raghavan Sheelakumari , Lesnick Timothy G. , Lowe Val J. , Machulda Mary M. , Knopman David S. , Petersen Ronald C. , Kantarci Kejal , Graff‐Radford Jonathan , Jack Clifford R. , Vemuri Prashanthi 
Published: December 2023

AbstractBackgroundNeurite orientation dispersion and density imaging (NODDI) measures from diffusion MRI provide information about tissue microstructure. Our goal was to compare the sensitivity of NODDI to structural MRI (sMRI) in capturing neurodegenerative changes in the gray matter due to aging and dementia.MethodWe included 815 participants [644 cognitively unimpaired (CU), 103 MCI, 68 AD] from the Mayo Clinic Study of Aging (MCSA) and Mayo ADRC with sMRI and multi‐shell diffusion MRI. We assessed gray matter volumes scaled by head size and cortical thicknesses from sMRI and neurite density index (NDI) and isotropic volume fraction (ISOVF) from NODDI. Pairwise Spearman correlations were calculated between imaging measures and Tau‐PET SUVRs in Braak I‐II, III‐IV, and V‐VI regions of interest (ROI) in participants = 60 years. Separate multivariable linear regression models were fit for the prediction of brain age using sMRI and NODDI in 515 CU participants. The predicted age gaps were calculated as chronological age minus predicted age in the remaining participants. We compared age gaps computed by sMRI and NODDI using disease surrogates (APOE4 genotype, AD pathologies via PET, WMH via FLAIR‐MRI, vascular risk, cognition via MMSE).ResultBraak ROIs, sMRI, and NODDI measures were correlated. The correlations between ISOVF and Tau‐PET SUVRs were stronger than correlations between NDI, volume, and thickness and Tau‐PET SUVR (Fig.1). MMSE was more associated with ISOVF than Tau‐PET and other imaging measures. The sMRI regression models had a higher mean absolute error (MAE) of 4.13 years than NODDI models with an MAE of 4.02 years. The NODDI model better predicted age gap separation between CU, MCI, and AD compared to the sMRI model (Fig.2). The NODDI predicted age gap showed stronger correlations with global amyloid‐PET SUVR, meta‐ROI Tau‐PET SUVR, CMC, APOE4, and MMSE (Fig. 3).ConclusionNODDI, especially ISOVF, had stronger correlations with MMSE and Tau‐PET SUVRs across all Braak ROIs. The brain age prediction model trained using NODDI was more sensitive in detecting neurodegeneration changes than sMRI based on associations with disease surrogates. Our work suggests that NODDI in gray matter may be a more sensitive surrogate of neurodegeneration compared to sMRI.
Patient‐related benefits of amyloid PET imaging in unclear dementia: rationale and study design of the randomized ENABLE study
Authors: Grazia Alice , Spottke Annika , Boecker Henning , Daamen Marcel , Graf Erika , Sahlmann Jörg , Buchert Ralph , Mohnike Wolfgang , Mohnike Konrad , Kurth Jens , Jessen Frank , Krause Bernd J , Teipel Stefan 
Published: December 2023

AbstractBackgroundDementia detection rate is very low in German primary care, as well as internationally. Amyloid PET imaging can reliably clarify an unclear diagnosis of dementia or an uncertain diagnosis of Alzheimer’s Disease (AD), improving diagnostic confidence and patient management. At present, systematic evidence of such benefits is still lacking. The patient‐related benefits of amyloid PET imaging (ENABLE) study will test whether amyloid PET will have a benefit on patients' functional status. Here, we describe the design of ENABLE, a randomized controlled two‐armed coverage with evidence development study in Germany.MethodApproximately 1,126 patients from 20 German academic memory clinics with a clinical diagnosis of mild‐moderate dementia of unclear etiology or of AD with low diagnostic certainty will be included in the study. Those patients will be randomly assigned to amyloid‐PET or routine diagnostics (no amyloid‐PET) (see Figure). The primary endpoint is change from baseline in the ability to perform instrumental activities of daily living (IADL) at 18 months as measured by the Amsterdam IADL Questionnaire. Secondary endpoints include the change in diagnosis, diagnostic confidence, cognition and clinical outcomes of patients and caregivers up until 24 months. We will apply linear and mixed linear models to assess primary and secondary endpoints.ResultWe expect patients' and caregivers' quality of life to be improved after receiving an amyloid PET formal diagnosis, as this will result into timely pharmacological and non‐pharmacological interventions.ConclusionThis study will benefit physicians’ and payers’ decisions on the provision of health care for patients with dementia in Germany.
Spectral graph modeling reveals global slowing of neurophysiological network transmission in Alzheimer’s disease
Authors: Verma Parul , Ranasinghe Kamalini G , Prasad Janani , Cai Chang , Xie Xihe , Lerner Hannah M , Mizuiri Danielle , Miller Bruce L , Rankin Katherine P , Vossel Keith , Nagarajan Srikantan S , Raj Ashish 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia, progressively impairing memory and cognition. While various neuroimaging studies have revealed functional network abnormalities in patients with AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. In order to answer these questions, we employed a spectral graph‐theory based model (SGM) to identify abnormal biophysical markers of neuronal activity in AD.MethodSGM is an analytic model that describes how the long‐range fiber projections in the brain mediate and couple the excitatory and inhibitory activity of local neuronal subpopulations. Unlike other coupled models, the SGM is linear, available in closed‐form, and parameterized by a small set of global parameters. This facilitates their rapid and unambiguous inference which we performed here on a well characterized clinical population of patients with AD (N = 88) and a cohort of age‐matched healthy controls (N = 88). We estimated SGM parameters that best captured the regional magnetoencephalography (MEG) frequency spectra of patients with AD and age‐matched controls.ResultSGM was able to capture the regional MEG frequency spectra of patients with AD and healthy controls, specifically, the abnormal slowing of neural oscillations in AD (Fig 1A). Patients with AD have significantly elevated long‐range excitatory neuronal time constant (tG) compared to controls (p < 0.001). Time constant tG is also the most important feature for accurate classification of patients with AD from controls (Area Under Curve = 0.85; Fig 1B). Lastly, higher tG is negatively correlated with global cognitive decline score (p = 0.02; Fig 1C).ConclusionThese results indicate that a global impairment in the long‐range excitatory neuronal activity is associated with abnormal spectral signatures and cognitive deficits in AD. Intriguingly, our work is able to recapitulate the spatial and spectral patterns of AD‐related functional activity without introducing any spatial heterogeneity whatsoever; indeed, the SGM model is entirely global and spatially‐invariant. This raises the possibility that a global increase in the long‐range excitatory time constant might be a sufficient factor underlying observed spatiotemporal alterations of neuronal activity in AD. Our findings provide new insights into potential mechanistic links between abnormal neural oscillations and their cellular correlates in AD.
Neuroimaging of new and novel Alzheimer’s Disease (AD) mice from the MODEL AD Consortium
Authors: Obenaus Andre , Stark Craig E.L. , Wu Yu‐Chien , Territo Paul R 
Published: December 2023

AbstractBackgroundThe ability of preclinical neuroimaging in rodent models of Alzheimer’s Disease and Related Dementia (ADRD) to assess the progression of disease is increasingly providing novel insights into AD, like human AD imaging. Preclinical studies have the advantage of being able to directly correlate findings to the observed neuropathology. Recently, University of California Irvine and Indiana University School of Medicine along with Jackson Laboratories were awarded funding to design and phenotype relevant mouse models of late onset AD (LOAD), forming the MODEL AD consortium (https://www.model‐ad.org/). Imaging cores from these will utilize existing state of the art translationally relevant medical imaging methodologies as well as ascertain feasibility of emerging imaging methods for increased diagnostic sensitivity.MethodTwo primary imaging modalities will be utilized: high‐field MRI (9.4T and 17.6T) and PET/CT. Deep MRI phenotyping are based on the accepted human‐AD standards like ADNI (Structural T2W, FLAIR, diffusion, perfusion (PWI), susceptibility, and functional MRI and MR spectroscopy). Novel histological vessel painting combined with PWI will assess vascular modifications. PET imaging will evaluate brain metabolism (18F‐FDG), regional perfusion (64Cu‐PTSM), amyloid (18F‐AV45), tau (18F‐AV1451), neuroinflammation (18F‐CPPC and 18F‐GSK1482160), and astrogliosis (18F‐FEBU) markers in new mouse models.ResultMODEL AD consortia will utilize platform mice (Table 1) across their lifespans and effects after being fed a high fat diet. Known and emerging GWAS risk variants for AD will be added to these platform mice to better replicate human AD. Neuroimaging data will be presented from PET/CT and MRI, focusing on exemplars from relevant AD mouse models including platform mice. A long‐term goal of the MODEL‐AD Imaging cores is to co‐register MRI, PET/CT and vascular measures to concordant histopathological and spatial RNA data. The cores have developed state‐of‐the‐art analytical pipelines to process imaging data to support spatial and temporal localization of ADRD.ConclusionThe MODEL AD consortium (UCI/IUSM/Jax) will develop new and novel AD mouse models and the imaging cores will deeply phenotype these models using existing and emerging neuroimaging methods and analytic approaches, using MRI and PET/CT. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).
Association of plasma Alzheimer’s and neurodegenerative disease biomarkers with brain volume loss and cognitive decline
Authors: Dark Heather E , Duggan Michael R , An Yang , Bilgel Murat , Joynes Cassie , Lewis Alexandria , Moghekar Abhay , Resnick Susan M. , Walker Keenan A. 
Published: December 2023

AbstractBackgroundAlthough plasma Alzheimer’s disease (AD) and neurodegenerative disease biomarkers have been associated with reduced cognition and lower brain volume, few studies have examined whether plasma biomarkers measured in predominately cognitively unimpaired adults are associated with longitudinal brain volume loss and cognitive decline. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of AD pathology (Aß42/40, phosphorylated tau [pTau‐181]), reactive astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline.MethodPlasma biomarkers (Aß42/40, pTau‐181, GFAP, NfL) were measured using Quanterix SIMOA assays. Baseline visits were considered the earliest visits that had concurrent 3T MRI scans and plasma biomarker measurements, and the earliest visits that had concurrent cognitive assessments and plasma biomarker measurements. Composite Z scores were computed to reflect 5 cognitive domains (Figure 1). Linear mixed effects models adjusted for baseline age, sex, race, education, estimated glomerular filtration rate, and total intracranial volume (brain volume analyses), were used to examine the association of plasma biomarkers with baseline and longitudinal brain volume and cognition. False Discovery Rate correction was used to adjust for multiple comparisons.ResultBrain volume analyses included 628 participants (mean age±SD: 71.0±10.2; Table 1) with an average of 3.3 MRI scans over 4.7 years. Cognition analyses included 686 participants (mean age±SD: 71.4±10.1) with an average of 3.9 cognitive assessments over 5.7 years. Although Aß42/40 was unrelated to brain volume changes, higher pTau‐181 was associated with longitudinal declines in total gray matter volume and regional declines in medial temporal regions. Higher GFAP was associated with longitudinal increases in ventricular volume, whereas NfL was not associated with brain volume change (Table 2). Both lower Aß42/40 and higher pTau‐181 were associated with a decline in verbal memory. Additionally, lower Aß42/40 was associated with a decline in visuospatial performance. Further, higher GFAP was associated with a decline in verbal fluency (Figure 1).ConclusionPlasma biomarkers of AD pathology and astrogliosis may serve as markers of future brain atrophy and cognitive decline.
Alzheimer’s disease biomarkers of amyloid and tau influence white matter neurite alterations in dementia with Lewy bodies: a NODDI study
Authors: Mak Elijah , Reid Robert I. , Przybelski Scott A. , Lesnick Timothy G. , Schwarz Christopher G. , Senjem Matthew L. , Raghavan Sheelakumari , Vemuri Prashanthi , Jack Clifford R. , Min Hoon‐Ki , Jain Manoj K. , Miyagawa Toji , Forsberg Leah K. , Fields Julie A. , Savica Rodolfo , Graff‐Radford Jonathan , Jones David T. , Botha Hugo , St Louis Erik K , Knopman David S. , Ramanan Vijay K , Graff‐Radford Neill R , Ferman Tanis J , Petersen Ronald C. , Lowe Val J. , Boeve Brad F. , O'Brien John T , Kantarci Kejal 
Published: December 2023

AbstractBackgroundCo‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐ß plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.MethodConsecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.ResultCompared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.ConclusionWidespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐ß deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.