bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effects of Hypertension on White Matter Microstructural and Vascular Imaging Metrics
Authors: Kim Donghoon , Hughes Tim M. , Wu Yu‐Chien , Lockhart Samuel N. , Craft Suzanne , Baker Laura D , Whitlow Christopher T. , Okonmah‐Obazee Stephanie E. , Hugenschmidt Christina E , Bobinski Matthew , Jung Youngkyoo 
Published: December 2023

AbstractBackgroundHypertension is one of the key vascular risk factors of AD and related dementia. Cerebral blood flow (CBF) and white matter (WM) integrity may play an essential role in understanding the vascular contributions to dementia (VCID). We investigated if hypertension is related to WM microstructural and vascular imaging metrics in WM.MethodFour‐hundred‐seven subjects (age: 69.7±8.1 years) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core underwent MRI, including neurite orientation dispersion and density imaging (NODDI) and eight‐phase pseudo‐continuous ASL (PCASL). The subjects included 158 MCI, 111 APOE e4 allele carriers, 224 with hypertension, and 249 with impaired glycemic status which includes type 2 diabetes and prediabetics. Hypertension status was defined as SBP = 130mmHG and DBP = 80mmHG. The microstructural imaging metrics including intracellular volume fraction (ICVF), isotropic volume fraction (ISOVF), and orientation dispersion index (ODI) were obtained from NODDI. The vascular imaging metric included CBF. CBF was obtained from PCASL sequence. Voxel‐wise linear regression analyses were performed to examine if CBF, ICVF, ISOVF, or ODI were related to hypertension adjusting for cognitive status, glycemic status, APOE e4 allele, age, sex, and years of education. All images were normalized into standard space. Tract‐based spatial statistics (TBSS) were used to normalize NODDI images. The false positive cluster thresholding was applied.ResultHypertensive subjects showed impairments in both microstructural and vascular imaging metrics. Based on Figures 1‐(A), 2‐(A) and 3‐(A), there are overlapping brain image voxels between the microstructural and vascular imaging metrics. Additionally, the hypertensive subjects showed significantly lower CBF, higher ISOVF, and higher ODI than normal subjects within the voxel clusters (Figures 1‐(B), 2‐(B), and 3‐(B)). Note that APOE e4 allele, glycemic status, and cognitive status also showed statistical significance in the NODDI parameters, but there was no association in CBF.ConclusionHypertension showed the potential association between the microstructural and vascular impairments in the WM. Each risk factor and cognitive status differently affected WM microstructural and vascular dynamic imaging parameters. These findings warrant further investigations of contributions of hypertension to the microstructural and vascular abnormalities in dementia.
Posterior Primary Progressive Prosopagnosia: Imaging and Neuropathology
Authors: Appleton Johanna , Bradbury Kathleen , Shyer Madison , Finn Quentin , Arbones Victoria , Dickerson Brad C. , Cykowski Matthew D , Masdeu Joseph C. , Pascual Belen 
Published: December 2023

AbstractBackgroundProsopagnosia is common with right temporal lesions, often in the fusiform gyrus when caused by vascular pathology. When caused by frontotemporal dementia, the lesion typically begins in the temporal tip. We are reporting advanced imaging, including tau and inflammation, as well as neuropathology in a patient with pathology centered at the posterior extent of the fusiform gyrus.MethodA 69‐year‐old man with apperceptive prosopagnosia and a negative amyloid positron emission tomogram (PET) underwent MRI and PET using 11C‐PBR28, an inflammation tracer, and 18F‐flortaucipir. VT values for 11C‐PBR28 were calculated with the Logan plot and a metabolite‐corrected arterial input function. For 18F‐flortaucipir, the SUV ratio over the cerebellar gray matter was calculated for t = 80‐100 min. A neuropathological examination was conducted using standard procedures as well as phospho‐tau histochemistry.ResultAtrophy and 18F‐flortaucipir uptake involved a similar region at the posterior extent of the right fusiform gyrus and, minimally, a symmetrical region of the left fusiform gyrus and an area in right premotor cortex. Involving the same regions, the 11C‐PBR28 signal was however more extensive than atrophy or 18F‐flortaucipir signal. At autopsy, the patient had corticobasal degeneration (CBD), with severe 4R tau involvement of temporo‐occipital, inferior parietal, and frontal cortices, as well as limbic regions and subcortical nuclei. The location of CBD pathology in this patient was highly atypical, as shown by comparing the neuropathological findings with the findings in two typical CBD patients.ConclusionAlthough prosopagnosia from ischemic and other lesions in the right posterior temporo‐occipital region is common, primary progressive prosopagnosia in the absence of amyloid has been described mostly with involvement of the right anterior temporal region. As exemplified by our patient, it can rarely happen with posterior temporal involvement and in this case the pathology was not TDP‐43 type C, as present in most patients with anterior temporal involvement, but corticobasal degeneration, a 4R tauopathy.
Sleep Quality and Day‐to‐Day Variability: Relation to Alzheimer’s pathology in Cognitively Unimpaired Older Adults At‐Risk of AD Dementia
Authors: Mohammediyan Bery , Baril Andree‐Ann , St‐Onge Frederic , Ourry Valentin , Carrier Julie , Breitner John C.S. , Poirier Judes , Villeneuve Sylvia 
Published: December 2023

AbstractBackgroundIncreasing evidence suggests a link between sleep and late‐life Alzheimer disease’s (AD) pathology. We investigated whether sleep degradation might be accompanied by faster AD pathology accumulation and/or whether early AD pathologic changes might be accompanied by sleep changes before the onset of cognitive symptoms.MethodWe investigated 228 PREVENT‐AD participants with available sleep data who underwent Aβ, [18F] NAV‐4694, and tau,[18F] Flortaucipir, positron emission tomography (PET). Longitudinal subjective sleep quality data were available for 191 participants (follow‐up:1.03±0.19y), longitudinal objective sleep data measured with actigraphy was available for 152 participants (follow‐up:2.5±1.24y), and longitudinal PET scans were available for 104 participants (follow‐up:4.3±0.24y). We assessed sleep quality using the Pittsburgh sleep quality index (PSQI) global score along with 7‐day actigraphy to indicate sleep duration, efficiency, and fragmentation index. Daily variation in sleep was measured using cross‐sectional and longitudinal standard deviations across the 7 days of actigraphy. Linear mixed effect models tested for longitudinal association of baseline sleep measures with PET outcomes over time. We also examined whether an increase in PET AD tracer uptake predicted changes in sleep quality and day‐to‐day variability. Every model controlled for age and sex.ResultWe found no association between sleep measures and Aβ PET. Higher baseline PSQI scores were associated with higher levels of tau over time (p = 0.004, R2 = 0.034, 𝛽 = 0.007, Fig.1, A). Higher baseline variability of sleep duration and fragmentation index were also associated with higher levels of tau longitudinally (p = 0.001, R2 = 0.05, 𝛽 = 0.001, Fig.1, B; p = 0.029, R2 = 0.022, 𝛽 = 0.01; Fig.1, C). Furthermore, increased tau at baseline was associated with lower sleep quality (p = 0.006, R2 = 0.026, 𝛽 = 4.12, Fig.2, A), and with higher sleep duration variability over time (p = 0.004, R2 = 0.06, 𝛽 = 61.56, Fig.1, B.)ConclusionPoor sleep quality and higher day‐to‐day sleep variability in older age could contribute to faster rate of tau pathology accumulation, which could in turn disrupt sleep further. Targeting sleep disturbances may therefore serve in delaying tau burden and slowing down disease progression.
Blood‐brain barrier disruption measured by dynamic contrast‐enhanced MRI in Alzheimer’s disease
Authors: Rauchmann Boris‐Stephan , Toth Hannah , Guersel Selim Üstün , Schirge Philine , Schweiger Meike , Brendel Matthias , Franzmeier Nicolai , Lamby Niclas , Burow Lena , Kurz Carolin Isabella , Koriath Carolin , Tato Maia , Papazov Boris , Moussiopoulou Joanna , Pogarell Oliver Michael , Keeser Daniel , Dietrich Olaf , Stöcklein Sophia , Seelos Klaus , Perneczky Robert 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the accumulation of amyloid beta (Aß) plaques in the brain. Blood‐brain barrier (BBB) dysfunction has been associated with AD. Aß‐plaques have been found to disrupt the BBB, leading to increased permeability and invasion of immune cells into the CNS and triggering an inflammatory response, and contributing to neurodegeneration. In this study, we investigated BBB disruption in Alzheimer’s disease and its associations with amyloid deposition and clinical severity, and cognitive decline.MethodIn this cross‐sectional study, n = 16 AD patients were included. AD patients were defined as amyloid positive by CSF amyloid‐ß42/amyloid‐ß40 ratio < 5,5% and a Mini‐Mental‐State Examination (MMSE) score < 27. Dynamic contrast‐enhanced magnetic resonance imaging (DCE MRI), a non‐invasive imaging technique that uses intravenously injected gadolinium to quantify the permeability of the BBB has been acquired. DCE‐MRI quantification was quantified using the Patlak method. To analyse the regional degree of BBB disruption the AAL atlas was warped onto the Patlak maps and the median of each ROI was calculated. The cortical amyloid deposition has been quantified using 18F]flutemetamol ß‐amyloid‐PET and cognitive performance was assessed using the Alzheimer’s Disease neuropsychological battery (CERAD‐NB). Associations were tested using linear regression models adjusted for age and sex in SPSS.ResultThe highest Ktrans values were measured in the orbitofrontal cortex (mean: 1,6×10‐3 min‐1). BBB dysfunction in median Ktrans values in the bilateral temporal lobe and particularly the right hippocampus were associated with decreases in the CSF amyloid‐ß ratio. Furthermore, BBB dysfunction was negatively associated with cognitive decline measured by the CERAD‐NB. BBB dysfunction overlapped with amyloid PET accumulation in the parietal and temporal brain regions.ConclusionDCE MRI shows spatially localized BBB dysfunction in AD. The BBB dysfunction seems to be more severe in regions of the brain that are affected by Aß plaques. This could support the idea that Aß plaque contributes to BBB dysfunction in AD. BBB dysfunction also tends to be pronounced in patients with more severe cognitive impairment, suggesting that it may play a role in the progression of AD.
CSF sTREM2 and YKL‐40 modify the balance between soluble and fibrillary β‐amyloid in non‐demented individuals
Authors: Cacciaglia Raffaele , Falcon Carles , Shekari Mahnaz , Salvadó Gemma , Milà‐Alomà Marta , Kollmorgen Gwendlyn , Carboni Margherita , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo 
Published: December 2023

AbstractBackgroundCerebrospinal fluid (CSF) Aβ concentrations and Positron Emission Tomography (PET) imaging provide information of two different Aβ pools. Identifying the factors affecting the balance between soluble and deposited Aβ may inform on the mechanism of cerebral Aβ aggregation. Microglia and astroglia respond to Aβ pathology, yet their role in promoting the aggregation of Aβ plaques is unclear. We addressed whether CSF sTREM2 and YKL‐40 modulate the association between soluble and deposited Aβ in a cohort of middle‐aged cognitively unimpaired (CU) individuals.MethodThe first consecutive 320 CU individuals of the ALFA+ study with a [18F]flutemetamol (FTM) PET scan and CSF samples were included. CSF Aβ40, Aβ42, sTREM2, and YKL‐40 were measured with the Roche NeuroToolKit robust prototype immunoassays (Roche Diagnostics International Ltd). Standardized uptake value ratio images were calculated and a voxel‐wise regression was performed to predict FTM uptake. The interaction terms between CSF Aβ42/40 and either CSF sTREM2 or YKL‐40 served as predictors, while adjusting for age, sex, years of education, and APOE‐ε4. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels.ResultTable 1 describes the sample’s characteristics. As expected, CSF Aβ42/40 concentrations were negatively associated with Aβ PET uptake in widespread areas of the brain, but this association was modified by CSF sTREM2 and YKL‐40. Higher levels of CSF sTREM2 were associated with a reduced Aβ PET uptake for any level of CSF Aβ42/40 in the hippocampus bilaterally. Conversely, higher CSF YKL‐40 related to a higher Aβ PET uptake as a function of CSF Aβ42/40 in the precuneus, prefrontal cortex, and inferior parietal areas.ConclusionIn CU individuals, microglia and astroglia reactivity modify the association between soluble (CSF) and deposited (amyloid PET) Aβ. While TREM2‐mediated microglial response (as measured by CSF sTREM2) may prevent Aβ deposition in individuals with decreased soluble Aβ, astroglial reactivity (as measured by CSF YKL‐40) may have the opposite effect.
APOE4 affects cortical microstructural alterations in Alzheimer’s disease: evidence from an autopsy‐confirmed cohort
Authors: Torso Mario , Ridgway Gerard R , Valotti Michele , Hardingham Ian , Chance Steven A 
Published: December 2023

AbstractBackgroundApolipoprotein E e4 (APOE4) is one of the most studied genetic risk factors for developing Alzheimer’s disease (AD). However, it is still not fully understood how APOE4 contributes to cortical neurodegeneration. We investigate ante‐mortem cortical microstructural changes in carrier and non‐carrier patient MRIs with autopsy‐confirmed Alzheimer’s disease neuropathological changes (ADNC).MethodForty‐nine participants with ADNC and ante‐mortem MRI were obtained from the National Alzheimer’s Coordinating Center (NACC; n = 34) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 15). Participants were grouped based on APOE4 presence (22 non‐carriers and 27 carriers). Thal phase, CERAD neuritic plaque assessment, Braak NFT, and combined ABC score, were used as AD neuropathological hallmarks. Structural and diffusion MRI (dMRI) were used to calculate cortical diffusivity measures in five different functional macroregions: Primary Sensory, Unimodal, Limbic/Proisocortex, Heteromodal and Primary Motor (Ffytche & Wible 2014, PMID:24936089; Mesulam 1998, PMID:9648540). For each macroregion, cortical mean diffusivity and three neuropathology‐inspired cortical diffusivity measures were calculated: 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+) (Torso et al. 2022, PMID:36281682). Clinical, demographic and neuropathological data were used to characterize groups (Table). Group differences in diffusion metrics were tested with GLM adjusting for ABC score, interval between MRI scan date and autopsy date, scanner manufacturer, dMRI b‐value, age and sex, with false discovery rate correction (pFDR<0.05).ResultThe cortical diffusivity investigation revealed higher Primary Sensory (auditory, visual, sensory) AngleR values in APOE4 carriers (Figure). The APOE4 carrier group was significantly younger and showed higher Thal phase, CERAD neuritic plaque, Braak stage and ABC scores.ConclusionCortical diffusivity measures can detect differences in cortical microstructure of APOE4 Carrier and Non‐carrier patients, suggesting a wider pattern of cortical damage in APOE4 carriers that involves Primary Sensory areas (lateral occipital, postcentral, pericalcarine, transverse temporal). Consistent with previous findings, the diffusion‐derived metric AngleR appears particularly sensitive to subtle effects, such as the early cortical changes associated with amyloid deposition and neuroinflammation (Torso et al. 2022, PMID:36281682), perhaps linked to the APOE4 modulation of the pattern of cortical microstructural neurodegeneration.
Amyloid and tau pathology are associated with white matter properties in cognitively unimpaired older adults at risk of AD dementia
Authors: Qiu Ting , Rheault François , Soucy Jean‐Paul , Spreng R. Nathan , Binette Alexa Pichet , Descoteaux Maxime , Villeneuve Sylvia 
Published: December 2023

AbstractBackgroundWhite matter changes are hypothesized to be among the earliest changes occurring in the course of Alzheimer’s disease (AD). We investigated associations between AD pathology, namely amyloid and tau, and white matter microstructural changes in cognitively unimpaired individuals at risk of AD dementia. We expected higher levels of pathology to be related to lower free‐water‐corrected fractional anisotropy.MethodWe studied 223 cognitively normal older adults with PET and multi‐shell diffusion MRI from the PREVENT‐AD cohort. We first measured standardized uptake value ratios (SUVRs) in 40 brain regions for amyloid‐ß (Aß, i.e., lateral and medial prefrontal, parietal, lateral temporal, and cingulate cortical regions in both hemispheres) and 26 brain regions for tau (i.e., Braak stages I, III, and IV). We then used TractSeg, a deep learning framework, to segment 49 well‐established white matter bundles. We mapped free‐water‐corrected fractional anisotropy (FAT) in those bundles. Lastly, to explore the relationships between AD pathology and white matter microstructure across bundles, we applied two separate partial least squares analyses: one for Aß pathology and one for tau (Figure 1).ResultWe found one significant latent variable relating Aß pathology to FAT. Specifically, higher levels of Aß pathology were associated with the combination of higher levels of FAT within the rostral body of the uncinate fascicle and superior longitudinal fascicle (Figure 2A). We found two significant latent variables relating tau pathology to FAT for which higher levels of tau pathology were associated with elevated FAT within the uncinate fascicle, thalamo‐occipital bundle, optic radiation, inferior occipitofrontal fascicle, inferior longitudinal fascicle, middle longitudinal fascicle, etc. (Figure 2B).ConclusionIn cognitively unimpaired individuals at risk of AD, increased Aß and tau pathology were associated with higher levels of FAT in AD‐related bundles. These unexpected findings may suggest an inverted U‐shape pattern between AD pathology and FAT in the preclinical phase of AD for which FAT values would start by increasing before decreasing later in the course of the disease. This first increase might be a marker of early pathological processes such as neuroinflammation or swelling.
Medial Temporal Lobe White Matter Integrity is Related to Memory and Amyloid‐Beta Pathology in Aging
Authors: Parker Dana M , Adams Jenna N. , Taylor Lisa M. , Keator David B. , Sathishkumar Mithra , Harris Alyssa L. , McMillan Liv , Yassa Michael A. 
Published: December 2023

AbstractBackgroundDamage to white matter (WM) within the medial temporal lobe (MTL) may underlie memory decline in aging and Alzheimer’s disease (AD). We measured MTL WM tract integrity through diffusion tensor imaging and Neurite Orientation Dispersion and Density Imaging (NODDI). We tested WM integrity associations with memory performance and amyloid‐ß pathology in cognitively normal older adults.Method105 cognitively normal older adults (70.8 years old, 65% female) with diffusion MRI were processed with MRtrix3. Standard diffusion metrics of fractional anisotropy (FA) and mean diffusivity (MD) were calculated. NODDI MDT was used to generate the neurite density index (NDI), representing number of voxels with unhindered diffusion, and the orientation dispersion index (ODI), representing the variability of neurite orientation. We calculated these measures for MTL tracts from the JHU WM Atlas: cingulum‐hippocampus, fornix column/body, and fornix/stria terminalis. Participants received 18F‐florbetapir (FBP) to measure Aß pathology (n = 94), and global FBP SUVR was calculated. Memory was measured with the Rey Auditory Verbal Learning Test delayed recall score (RAVLT, n = 81). Analyses covaried for age and/or education.ResultBetter memory was associated with lower ODI in the fornix column/body (r = ‐0.27, p = 0.018), with trends for higher FA (r = 0.021, p = 0.06) and lower NDI (r = ‐0.19, p = 0.09). Better memory was also associated with higher MD in the cingulum‐hippocampus (right: r = 0.23, p = 0.04; left: r = 0.25, p = 0.03), with trends for lower ODI (right: r = ‐.20, p = 0.08; left: r = ‐0.20, p = 0.09). Higher FBP SUVR was associated with increased FA in the fornix column/body (r = 0.31, p = 0.003) and a trend in the left cingulum hippocampus (r = 0.20, p = 0.054). Memory or FBP SUVR was not significantly related to integrity of the fornix/stria terminalis.ConclusionIntegrity of fornix column/body and cingulum‐hippocampus were related to both memory performance and Aß pathology. Our results suggest that using a combination of NODDI as well as diffusion tensor metrics provided a more robust understanding of memory impacts in aging.
Amyloid‐, tau‐, and FDG‐PET in amyloid‐negative patients clinically diagnosed with early‐onset Alzheimer’s disease in the LEADS study
Authors: Mundada Nidhi S. , Soleimani‐Meigooni David N. , Zeltzer Ehud , Windon Charles , Tanner Jeremy A. , Heath Courtney Lawh , Iaccarino Leonardo , Shankar Ranjani , Amuiri Alinda , Aisen Paul S. S , Eloyan Ani , Koeppe Robert A. , Carrillo Maria C. , Dickerson Brad C. , Apostolova Liana G. , Rabinovici Gil D. , La Joie Renaud 
Published: December 2023

AbstractBackgroundNegative AD biomarkers are commonly found in patients with a clinical diagnosis of late‐onset AD, but little is known about biomarker‐negative patients diagnosed with sporadic Early Onset AD (EOAD, <65yo). We explored data from the Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) to identify such participants and explored amyloid‐, tau‐, and FDG‐PET.MethodWe identified 380 patients who i) met clinical criteria for MCI or dementia due to AD, and ii) completed baseline amyloid‐PET (Florbetaben) and tau‐PET (Flortaucipir). Of these patients, 93 (24.5%) were amyloid‐PET negative based on a combination of visual read and quantification (“EOnonAD”). A subset of EononAD participants completed FDG‐PET (n = 63), 5 had follow‐up amyloid‐PET and 2 had follow‐up tau‐PET. 63 age‐matched cognitively normal controls were also included. Image acquisition and processing followed ADNI protocols.ResultCompared to amyloid‐positive patients (EOAD), EononAD patients were less frequently female or APOE4 carriers, and less severely impaired (Figure 1). EononAD patients had a mean Centiloid of 5.6 (Figure 2A). At the group level, temporal Flortaucipir‐SUVR was low (1.20.3, not significantly different from controls), although 3 cases had Flortaucipir‐SUVR>2 (Figure 2A). Visual inspection showed these cases had asymmetric AD‐like Flortaucipir‐PET patterns (Figure 2B). Within patients with EononAD, amyloid‐ and tau‐PET were correlated (Spearman’s ρ = 0.29, p = 0.005), even when excluding the 3 high Flortaucipir‐SUVR outliers (Figure‐2C). 5 patients had follow‐up amyloid‐PET: 2 showed major amyloid‐PET increase (+20 CL over 3 years), exceeding the 25 CL threshold at follow‐up, while the other 3 remained amyloid‐negative (Figure 2D). Two patients had follow‐up Flortaucipir‐PET: a low‐Flortaucipir case remained low, and one of the three high‐tau cases showed increased signal over time (Figure 2D). Group‐level FDG‐PET analysis showed frontal, temporal, and/or parietal hypometabolism in EOnonAD (Figure 3A). However, individual maps showed high heterogeneity: while ∼50% showing no clear hypometabolism (normal‐looking FDG), the remaining cases showed heterogeneous patterns suggestive of various underlying etiologies (e.g., FTLD‐like or AD‐like patterns, Figure 3B).ConclusionAmyloid‐PET negative patients included in LEADS are heterogeneous. While a minority of cases might have underlying AD with subthreshold amyloid‐ and/or tau‐PET values, FDG‐PET showed heterogeneous patterns suggesting underlying etiologies include various degenerative and non‐degenerative causes. ”