bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma biomarkers in relation to spatial distribution of Alzheimer’s disease neuropathology
Authors: Bilgel Murat , Shah Ishaan , Walker Keenan A. , Moghekar Abhay , Ashton Nicholas J. , Kac Przemyslaw Radoslaw , Karikari Thomas K , Blennow Kaj , Zetterberg Henrik , Thambisetty Madhav , Ferrucci Luigi , Resnick Susan M.
Published: December 2023

Background

The clinical utility of plasma biomarkers will in part be based on the information they convey regarding the distribution of neuropathology, especially beyond the information provided by demographics. We examined the associations of plasma biomarkers with cerebral amyloid and tau pathology determined by positron emission tomography (PET).

Method

In the Baltimore Longitudinal Study of Aging, plasma Aß42/Aß40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) concentrations were measured using Quanterix Simoa assays. Plasma concentrations of phosphorylated tau at threonine 181 (p‐tau181) and at 231 (p‐tau231) were measured using in‐house Simoa assays at University of Gothenburg. Using voxelwise linear regression models, we investigated cross‐sectional associations of plasma biomarkers with brain fibrillar amyloid and phosphorylated tau pathology as measured by PET with 11C‐Pittsburgh compound B (PiB) conducted on a GE Advance scanner (N = 189) and 18F‐flortaucipir (FTP) conducted on a Siemens High Resolution Research Tomograph (N = 107), respectively. In addition to unadjusted analyses, we conducted analyses adjusting for age, sex, and race. Results were corrected for multiple comparisons using permutation test‐based threshold‐free cluster enhancement (TFCE).

Result

Lower plasma Aß42/Aß40 was associated with higher PiB distribution volume ratio (DVR) in the unadjusted model, but not in the adjusted model (Figure 1). The remaining plasma biomarkers exhibited statistically significant positive associations with PiB DVR in both unadjusted and adjusted models. The plasma biomarker with the strongest and most widespread association with PiB DVR was p‐tau231 (Figure 2). Both p‐tau biomarkers exhibited statistically significant associations with FTP standardized uptake value ratio (SUVR) in both unadjusted and adjusted models. Aß42/Aß40, GFAP, and NfL did not exhibit statistically significant associations with FTP SUVR. Associations of p‐tau biomarkers with PiB DVR were stronger and more widespread than with FTP SUVR. We did not find any statistically significant associations when we repeated the analyses separately by binary PiB group.

Conclusion

Plasma biomarkers convey information beyond age, sex, and race in relation to the cerebral distribution of amyloid, and to a lesser extent, tau. The smaller sample size of our FTP PET study might in part explain the weaker associations we observed with FTP SUVR compared to PiB DVR.
Associations of Age and Sex with Levels of Tau PET in Screened Participants from Auτonomy, a Phase 2 Anti‐p‐tau Monoclonal Antibody Trial in Early Symptomatic Alzheimer’s Disease
Authors: Kolb Hartmuth C. , Fedgchin Maggie M , Quiceno Mary Ellen , Henley David , Saad Ziad S.
Published: December 2023

Background

The ongoing Autonomy trial (NCT04619420) enrolls participants presenting with mild cognitive impairment (MCI) or mild AD dementia with a CDR Global Score of 0.5 and who are tau PET positive. The Janssen plasma p217+tau assay is used as a pre‐screen for eligibility to proceed to tau PET to reduce participant burden and improve screening efficiency. Using preliminary screening data available to date we report on associations of age and sex with tau PET, a biomarker for neurofibrillary tangle (NFT) burden, and with plasma p217+tau levels.

Method

18F‐MK6240 Tau PET SUVRs for 355 screened participants (180 female) were quantified in Braak Regions Of Interest (ROI)[1] 1 through 6 using cerebellar gray as reference region. Associations were analyzed using a linear model of regional SUVR as a function of age and sex. Additionally, models of association for plasma p217+tau in log(pg/ml) were considered.

Result

Age at baseline was not different (p>0.5) for female (70.84 y) versus male (70.49 y) participants. For Braak 3 ROI, tau PET SUVRs showed significant negative association for age (R2partial = 16%, p<10‐14), and increased levels in females (R2partial = 2%, p<0.01). The results were qualitatively similar across Braak ROIs 1 through 4. For Braak ROIs 5, and 6, the effect of sex was no longer significant, although the trend remained in a consistent direction. For plasma p217+tau, we found significant negative association for age (R2partial = 7%, p<10‐6) and a trend for higher levels in female participants (R2partial = 1%, p = 0.05).

Conclusion

In early Alzheimer’s disease participants who were screened with tau PET for the ongoing Autonomy trial, higher SUVR was observed for younger versus older participants and in females versus males. The effect of age is likely due to the cohort’s cognitive uniformity whereby in younger participants, a higher tau burden as measured by PET is required for the same level of impairment as older participants[2]. The increased tau PET NFT levels observed in female participants is consistent with findings by Edwards et al. [3]. Associations of similar directions were also observed for plasma p217+tau. [1] Schöll et al., Neuron 2016. [2] Jack et al., Brain 2018. [3] Edwards L et al., Neurobiology of Aging 2021
Interventional clinical trial findings from targeted multiday repetitive transcranial magnetic stimulation to treat memory loss in amnestic mild cognitive impairment
Authors: Warren David E , Phipps Connor J , Heller Abi , Behm Lillian , Zatkalik Abigail L , Wilhelm Anna F , Phatak Vaishali S , Murman Daniel L
Published: December 2023

Background

Memory loss is the hallmark cognitive symptom of Alzheimer’s disease (AD), and it affects independence, autonomy, and identity. AD‐related memory deficits are associated with pathological changes in brain structure and function, and current treatments offer limited relief. Targeted repetitive transcranial magnetic stimulation (rTMS) of AD‐vulnerable intrinsic brain networks can enhance memory abilities in healthy adults (Wang et al., 2014). To test rTMS approaches as a potential treatment for clinical memory loss, we administered a local clinical trial (ClinicalTrials.gov #alz081816) that enrolled patients with amnestic mild cognitive impairment (aMCI), a frequent precursor to AD (target enrollment of 16). Here, we report cognitive and brain findings from our trial.

Method

Patients with aMCI completed two weeklong interventions consisting of pre‐stimulation brain and cognitive measurement, rTMS for five consecutive days, and post‐stimulation brain and cognitive measurement. Brain measures included structural and resting‐state functional MRI data; cognitive assessments included measures of memory function. Interventions were identically formatted except for rTMS intensity (treatment/sham). Stimulation used ß‐frequency pulse sequences which alternated 2‐sec. 20 Hz stimulation with 28‐sec. rest for 20 min (1600 pulses); stimulation location was a left lateral parietal cortex location coactive with a hippocampus‐centered functional network. Stimulation intensity varied with each participant’s resting motor threshold (treatment, 100%; sham, 10%). Condition order was counterbalanced.

Result

We identified hippocampus‐centered networks in each participant, then localized parietal rTMS targets. Critically, we observed changes in brain and cognitive (memory) measures in the treatment‐intensity condition that were not observed in the sham‐intensity condition. Furthermore, we observed changes in intrinsic network connectivity within the stimulated hippocampus‐centered network.

Conclusion

Our trial of patients with aMCI measured changes in brain and cognitive variables after rTMS of a brain network supporting memory processes. We found evidence consistent with neural plasticity, and we frequently observed memory improvement in patients with aMCI after treatment‐intensity rTMS. Our findings suggest that rTMS can improve memory in clinical populations. This is important because, counterintuitively, new disease modifying therapies for AD may increase need for symptomatic treatment of memory loss due to prolongation of prodromal/mild stages of AD. Thus, adjuvant therapies such as rTMS for memory loss could improve AD treatment outcomes.
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

Background

Hypertension 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.

Method

Four‐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.

Result

Hypertensive 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.

Conclusion

Hypertension 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

Background

Prosopagnosia 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.

Method

A 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.

Result

Atrophy 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.

Conclusion

Although 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

Background

Increasing 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.

Method

We 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.

Result

We 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.)

Conclusion

Poor 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

Background

Alzheimer’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.

Method

In 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.

Result

The 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.

Conclusion

DCE 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

Background

Cerebrospinal 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.

Method

The 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.

Result

Table 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.

Conclusion

In 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

Background

Apolipoprotein 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).

Method

Forty‐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).

Result

The 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.

Conclusion

Cortical 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

Background

White 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.

Method

We 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).

Result

We 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).

Conclusion

In 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

Background

Damage 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.

Method

105 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.

Result

Better 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.

Conclusion

Integrity 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

Background

Negative 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.

Method

We 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.

Result

Compared 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).

Conclusion

Amyloid‐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. ”
Using neuroimaging biomarkers to define plasma thresholds in a community dwelling cohort
Authors: Rudolph Marc D. , Sutphen Courtney L. , Register Thomas C. , Whitlow Christopher T. , Sai Kiran K. Solingapuram , Hughes Timothy M. , Bateman James R. , Dage Jeff L. , Russ Kristen A. , Mielke Michelle M. , Craft Suzanne , Lockhart Samuel N.
Published: December 2023

Background

AD Imaging biomarkers (IBM) include measures of amyloid (A) on PET, and neurodegeneration (N) on MRI, with thresholds for classification of imaging A/N positivity commonly used at research centers. Novel AD plasma biomarkers (PBM) can potentially enhance neuropathological characterization; however, knowledge regarding which thresholds to use to characterize PBM abnormalities is limited.

Method

We evaluated a range of PBM thresholds based on (1) plasma data alone (gaussian mixture models [GMM]), and (2) when classifying A/N IBM using both existing and data‐driven cutoffs (ROC analyses). Baseline plasma and imaging data were obtained in a community‐dwelling cohort enrolled in the Wake Forest ADRC, including cognitively normal participants (N = 300) and individuals with consensus diagnosis of mild cognitive impairment (N = 192) or dementia (N = 64; Table 1). We examined PBMs (Quanterix SIMOA HD‐X from NCRAD: Aß42/40, GFAP, NfL, p‐tau181) and IBM measures of A (global PiB PET; A+>1.21 SUVR) and N (FreeSurfer temporal cortical thickness; MAYOTHCK), N+ = 2.68mm; FreeSurfer hippocampal volume, N+ = 0.454% head size; HPC‐VOL).

Result

Optimal/low/high GMM‐derived thresholds based on PBM distributions (Figure 1a) are provided in Figure 1b. ROC analysis using existing IBM cutoffs are in Figure 1c, with details (sensitivity/specificity/AUC) in Figure 1d. GMM‐ and ROC‐derived p‐tau181 thresholds were highly aligned (range 3.698‐4.071 pg/ml). For NfL and GFAP, imaging ROC‐derived thresholds were lower than GMM‐derived thresholds. AUCs were highest when PBM classification was used to predict A‐PET using existing PET‐positivity cutoffs, with PBM performing more poorly for MRI‐based cutoffs. A/N IBM histograms and current/optimal/low/high GMM‐derived thresholds for each IBM are in Figure 2a. Figure 2b represents how different data‐driven IBM cutoffs impact PBM thresholds in ROC analyses, with AUC statistics for these ROC analyses in Figures 2c‐e. Notably, GMM‐optimal IBM cutoffs performed similarly to current cutoffs for defining PBM thresholds, especially when using A‐PET (AUCs for current and GMM‐optimal >0.747).

Conclusion

While use of existing and data‐driven IBM cutoffs to define PBM thresholds in a community‐dwelling cohort is feasible, some plasma assays (e.g., p‐tau181) are more consistent than others, and caution is warranted against selecting a single threshold. To facilitate clinical use, future work will focus on establishing confidence intervals for PBM abnormalities.
The role of cerebrovascular pathology in the association between amyloid‐β and tau in cognitively unimpaired and impaired individuals
Authors: Coomans Emma M. , van Westen Danielle , Binette Alexa Pichet , Strandberg Olof , Spotorno Nicola , Palmqvist Sebastian , Stomrud Erik , Ossenkoppele Rik , Hansson Oskar
Published: December 2023

Background

Although cerebrovascular pathology often co‐exists with Alzheimer’s disease pathology, it remains incompletely understood to what extent it can contribute to the progression of Alzheimer’s disease pathology. We investigated whether cerebrovascular pathology (white matter lesions [WML] and microbleeds) modified the association between amyloid‐ß (Aß) and both cross‐sectional and longitudinal tau in cognitively unimpaired (CU) and cognitively impaired (CI) individuals.

Method

We included 1240 participants from the Swedish BioFINDER‐2 cohort including 402 Aß‐negative CU, 147 Aß‐positive CU, 257 Aß‐negative CI (MCI and non‐AD dementia) and 434 Aß‐positive CI participants (MCI and AD dementia) (Table 1). All underwent baseline [18F]RO948 (tau)‐PET, and a subset (n = 678) underwent longitudinal tau‐PET (2.6±1.0‐years). We extracted tau‐PET SUVr in a temporal meta‐region‐of‐interest. For Aß, we used global [18F]flutemetamol‐PET SUVr for CU and Aß‐status (+/‐) for CI participants. Global WML volume was calculated using the SPM lesion segmentation tool, corrected for intra‐cranial volume and log‐transformed. Presence of microbleeds was dichotomized into absent or present ( = 1) by visual read. Primary analyses included age‐, sex‐ and APOE e4‐corrected linear mixed models between tau‐PET (outcome) and interactions between time, Aß and WML volume/microbleeds (predictors).

Result

Upon correcting for age, sex and e4‐carriership, Aß‐positive CU and CI participants showed significantly more microbleeds compared to Aß‐negative participants of the same cognitive stage (both p<0.05), but no differences in WML volume was observed (both p>0.05). In CU, we observed a significant interaction effect between = 1 microbleed and higher Aß‐load with both greater cross‐sectional tau (ß = 0.67 [CI: 0.45‐0.89], p<0.001) and longitudinal tau (ß = 0.11 [CI: 0.07‐0.16], p<0.001) (Fig‐1, Table‐2). In CU, we also observed a significant interaction effect between larger WML volumes and higher Aß‐load with greater cross‐sectional tau (ß = 0.14 [CI: 0.06‐0.22], p = 0.001). When including both microbleeds and WML volume in the same model, only effects of microbleeds remained significant (Table‐2). No significant effects were observed in CI participants.

Conclusion

In CU (but not CI) individuals, cerebrovascular pathology may modify the association between Aß and tau by accelerating tau accumulation in the presence of Aß. These results might suggest an early effect of cerebrovascular pathology on the interplay between Aß and tau.
In vivo data‐driven patterns of Tau accumulation associated with AD progression using 18F‐MK‐6240 PET
Authors: Fonov Vladimir S , Nazneen Tahnia , Rosa‐Neto Pedro , Collins D Louis
Published: December 2023

Background

Alzheimer’s disease is a neurodegenerative disease associated with accumulation of amyloid beta and tau neurofibrillary tangles following a pattern known as Braak stages (Braak 1995,2011). Recent papers (Pascoal 2020) indicate possibility to recapitulate Braak histo‐pathological stages in vivo using tau tangles PET tracer 18F‐MK‐6240, using manually defined regions of interest. This study analyzes patterns of Tau accumulation associated with AD in a completely data‐driven fashion.

Method

We used T1w MRI and 18F‐MK‐6240 Pet scans from healthy controls in the community or outpatients at the McGill University Research Centre for Studies in Aging. The following number of datasets from each diagnostic group [n scans total (m unique participants)]: cognitively normal: 347(194), mild cognitive impairment: 163(99), Alzheimer’s disease dementia: 114(77). T1w MRIs were pre‐processed (non‐uniformity correction, intensity normalization, stereotaxic registration, brain masking, tissue classification); FALCON (Fonov 2020) was used to extract the mid‐cortical surface. PET scans were linearly registered to the T1w MRI and the standardized uptake value ratio (SUVR) was calculated using whole cerebellum grey matter as the reference. SUVR values were sampled along cortical mid‐surfaces and geodesically smoothed with a 10mm gaussian and resampled to the cortical surface of MNI2009c template (Fonov 2011).

Result

Figure 1 shows Mean SUVR values on top of Figure 1, and latent factors at the bottom. Overall low values of tau in the temporal, partial and occipital region are associated with normal cognition (F1). Tau changes in the temporal lobe (F2, similar to stage 1&2) are associated with a slight cognitive change. Change in parietal and posterior temporal areas (F3, similar to stage 3&4) are associated with even more cognitive loss. Finally changes in the motor strip and ventral portion of the occipital lobe and remaining cortex (F4 and F5) are associated with the very advanced stages (5&6) of cognitive decline.

Conclusion

We discovered patterns of tau accumulation associated with progression of cognitive decline in a completely data‐driven fashion.
Effect of SUVR reference region selection on sampled iterative local approximation estimates of amyloid onset age
Authors: Teague Jordan P , De Chavez Elena Ruiz , Irizarry‐Pagan Erica E , Cody Karly Alex , Asthana Sanjay , Johnson Sterling C , Christian Bradley T. , Langhough Rebecca E , Betthauser Tobey J
Published: December 2023

Background

Amyloid PET imaging quantifies Aß plaques informing longitudinal modeling methods such as sampled iterative local approximation (SILA) that provide individualized estimated amyloid onset age (EAOA). EAOA is defined as the transition to abnormal Aß accumulation that occurs in Alzheimer’s disease. This work investigates the effect of SUVR reference region selection on EAOA by comparing DVR‐trained versus SUVR‐trained SILA models with three different SUVR reference regions.

Method

N = 585 participants (mean (SD) baseline age = 66.40 (7.89) years, 512 unimpaired, 44 MCI, 28 dementia, 1 unknown) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center underwent T1‐weighted MRI and dynamic 11C‐Pittsburgh Compound B (PiB) amyloid PET imaging (0‐70 minutes after bolus injection). Reconstructed dynamic PET time series were processed and quantified using MR‐guided imaging pipelines optimized for DVR (Logan, k2’ = 0.149 min‐1, cerebellum gray matter (CBLM‐GM) reference region) and SUVR (50‐70 min frames) quantification with CBLM‐GM, whole cerebellum (WHOLE‐CBLM), or subcortical white matter (WM) as a reference region. Mean cortical PiB DVR and SUVR were each calculated by averaging across eight bilateral ROIs. Group‐based trajectory modeling was applied to longitudinal DVR data to establish an amyloid positivity (A+) threshold (DVR>1.14; equivalent to 14 centiloids). LME was used to define the relationship between DVR and SUVR and translate the DVR threshold to SUVR (SUVRCBLM GM>1.28; SUVRWHOLE CBLM>1.07; SUVRWM>0.68). Within‐person paired differences between EAOADVR and EAOASUVR_REFERENCE_REGION are reported as (mean; [95% CI]).

Result

EAOA derived from DVR and SUVR were compared for n = 198 (34%) DVR A+ participants. Amyloid vs. age data are shown for each quantification approach in Figure 1. EAOASUVR‐WHOLE‐CBLM (‐1.29 years; [‐1.51, ‐1.08]) had the highest agreement with EAOADVR compared to EAOASUVR‐CBLM‐GM (‐1.44 years; [‐1.75, ‐1.12]) and EAOASUVR‐WM (‐0.67 years; [‐2.13, 0.79]; Figure 2). EAOA variability was highest for DVR>1.8 where fewer longitudinal observations were available for model training.

Conclusion

SUVR with whole cerebellum as a reference region resulted in the smallest difference in EAOA compared to DVR from the SILA model. Future work is ongoing to define SUVR thresholds that will optimize agreement with DVR‐trained EAOA results for harmonization of temporal estimates.
Diffusion MRI free water in hippocampal subfields CA3 and CA1 tracks progression in prodromal and overt synucleinopathy
Authors: Huddleston Daniel , Langley Jason , Chen Xiangchuan , Tucker Kelsey , Littrell Kevin , Maan Saad , Hyland Sierra , Bliwise Donald , Hu Xiaoping
Published: December 2023

Background

Postmortem study of the hippocampal subfields in the Lewy body dementias has revealed selective involvement of CA3 with synuclein pathology and CA1 with amyloid and tau, i.e., Alzheimer’s disease (AD) co‐pathology (Coughlin et al., 2020, PMID:32892355). However, new neuroimaging methods are needed to study the hippocampal subfields in vivo in synucleinopathies. Diffusion MRI free water (FW) measurement detects increased hippocampal FW in AD (Ofori et al., 2019, PMID:31470214). However, typical diffusion MRI protocols have voxels = 2 mm3 making hippocampal subfield imaging infeasible due to volume averaging effects. To address this, we developed a high‐resolution diffusion MRI protocol capable of imaging the hippocampal subfields. We applied this approach to study a prodromal synucleinopathy group – idiopathic REM sleep behavior disorder (iRBD), as well as PD with normal cognition (PD‐NC), PD with cognitive impairment (PD‐CI), and dementia with Lewy bodies (DLB).

Method

Participants with PD‐NC, PD‐CI, DLB, and polysomnographically confirmed iRBD were recruited at Emory University. T1 MPRAGE (0.8mm3 voxels) and high‐resolution diffusion MRI (b = 0, 500mm2/sec; 30 diffusion directions; 1.1mm3 voxels) data were acquired with a Siemens 3T Prisma‐fit system. FreeSurfer v7 was used to segment hippocampal subfields. FW was measured as described in Ofori, et al (2017, PMID:28714593). Groups were compared using ANCOVA followed by post‐hoc tests, and clinical and MRI features were correlated.

Result

Table 1 shows group demographic and clinical characteristics. A progressive increase in CA3 and CA1 FW was observed from iRBD to PD‐NC to PD‐CI and DLB, and the ANCOVA model, controlling for age, found a statistically significant difference between groups for CA3 FW (Figure 1). Figure 2 shows statistically significant negative correlations between MoCA and hippocampal FW measures and between years of education and FW in CA3 and CA1.

Conclusion

CA3 and CA1 FW are significantly increased in advanced synucleinopathy (DLB, PD‐CI) as compared to iRBD, and PD‐NC has intermediate values. Strong negative correlations between CA3 and CA1 FW and cognition further indicate that these measures may track disease progression. The negative correlations between CA3 and CA1 FW and education also suggest that these measures may be biological correlates of cognitive reserve.