bluuebunny/crossref_metadata_2025 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

Background

The 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.

Method

White 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.

Result

Mean 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).

Conclusion

The 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

Background

The 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.

Method

Using 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.

Result

The 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).

Conclusion

The 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

Background

Carriership 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.

Method

375 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.

Result

APOE4 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.

Conclusion

The 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

Background

Neurite 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.

Method

We 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).

Result

Braak 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).

Conclusion

NODDI, 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

Background

Dementia 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.

Method

Approximately 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.

Result

We 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.

Conclusion

This 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

Background

Alzheimer’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.

Method

SGM 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.

Result

SGM 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).

Conclusion

These 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

Background

The 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.

Method

Two 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.

Result

MODEL 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.

Conclusion

The 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

Background

Although 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.

Method

Plasma 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.

Result

Brain 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).

Conclusion

Plasma 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

Background

Co‐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.

Method

Consecutive 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.

Result

Compared 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.

Conclusion

Widespread 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.
Striatal Amyloid deposition in sporadic Alzheimer’s Disease
Authors: Arena Julieta , Urrutia Leandro , de Leon Magdalena Ponce , Seminara Emiliana , Falasco German , Bérgamo Yanina , Allegri Ricardo Francisco , Sevlever Gustavo , Vazquez Silvia
Published: December 2023

Background

It has been shown that disorders associated with early‐life alterations in amyloid production or processing such as in autosomal dominant Alzheimer’s disease (AD) and down syndrome‐associated dementia have a different pattern of Aß deposition, with early striatal accumulation, as compared to sporadic late‐onset cases, in which striatal deposition has been suggested to be a marker of late and advanced amyloidosis. It is not clear, however, if the pattern of amyloid accumulation is related to any other factors or if it has any impact on brain metabolism. We aimed to determine if there are any clinical or demographic predictors of striatal tau accumulation in sporadic AD and whether its presence affects the subjects´ brain metabolism.

Method

Subjects that underwent positron emission tomography (PET) scans with 18F‐FDG and 11C‐PIB were analyzed retrospectively. Only those with clinical diagnosis of AD and mild cognitive impairment (MCI) due to AD were considered for the analysis. Visual analyses were performed to exclude subjects without cortical amyloid accumulation. Mean values from cortical volumes of interest (VOIs) and striatum were obtained. Amyloid deposition was correlated with age and disease duration via Pearson’s correlations. Amyloid deposition was also correlated to brain metabolism as assessed by FDG PET.

Result

150 subjects were included in this study. Neither age nor disease duration was correlated with striatal amyloid accumulation. Subjects with striatal Pib accumulation showed higher cortical amyloid burden. Moreover, higher striatal amyloid burden was positively correlated with higher frontal amyloid burden specifically. Amyloid burden in the striatum did not seem to have an impact on the glucose metabolism in the striatum itself. However, variations in cortical glucose metabolism could be observed. A higher striatal amyloid burden was correlated with cortical glucose hypometabolism, specifically in the precuneus and temporal areas (Figure 1).

Conclusion

There seems to be a stage of sporadic Alzheimer’s disease in which amyloid accumulates in the striatum. This, in turn, appears to have an impact on brain functioning. Whether this has a real impact on cognitive performance remains to be elucidated.
Cerebral amyloid angiopathy is associated with higher gray matter regional R2 relaxation rate: An ex‐vivo MRI and pathology study
Authors: Yasar Md Tahmid , Evia Arnold M , Bennett David A. A , Schneider Julie A , Arfanakis Konstantinos
Published: December 2023

Background

Cerebral amyloid angiopathy (CAA) is characterized by accumulation of amyloid‐ß (Aß) protein in the walls of cortical and meningeal small vessels. CAA is common in older adults. It has been linked to intracerebral hemorrhage and cognitive decline. In this study, the association of CAA with the transverse relaxation rate R2 values was investigated in gray matter regions from a large number of community‐based older adults.

Method

Cerebral hemispheres from 802 older adults participating in four cohort studies of aging, the Rush Memory and Aging Project, the Minority Aging Research Study, the Religious Orders Study, and the Clinical Core of the Rush Alzheimer’s Disease Research Center (Fig. 1a) were included in this work. All hemispheres were imaged ex‐vivo using 3T MRI scanners. R2 maps were generated from multi‐echo spin‐echo images. Gray matter was segmented into 34 cortical and 8 subcortical regions. Median R2 values were obtained from each region. Following ex‐vivo MRI, all hemispheres underwent detailed neuropathologic assessment (Fig. 1b). Evaluated neuropathologies included: CAA, Aß plaques, neurofibrillary tangles, gross infarcts, microinfarcts, TDP‐43 pathology, hippocampal sclerosis, Lewy bodies, atherosclerosis, and arteriolosclerosis. Multiple linear regression was conducted in each segmented gray matter region separately to test the association of the corresponding median R2 value with the global CAA score, controlling for all other neuropathologies, age at death, sex, education, postmortem interval to fixation and to imaging, and scanners. False discovery rate (FDR) was used to correct for multiple comparisons. Statistical significance was set at p<0.05.

Result

A significant positive association of median R2 with CAA pathology was found in several cortical regions of the temporal and frontal lobes as well as in subcortical structures (Fig. 2,3). No gray matter region showed lower median R2 for higher CAA score. Furthermore, we obtained similar findings when also controlling in the linear regression models for normalized regional volume and for clinical variables such as history of hypertension, diabetes, smoking, blood pressure levels, and the presence of the APOE‐e4 allele.

Conclusion

This investigation showed that CAA is independently associated with elongated R2 in cortical regions of the temporal and frontal lobes as well as in subcortical structures.
Cerebral perfusion is elevated in a novel model of aged hAβKI APOE4 mice
Authors: Obenaus Andre , Singh Aditya , Pad Rojina , Iyer Anika , Ketsan Tia , Jullienne Amandine
Published: December 2023

Background

The Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL‐AD has generated a new human Aß Knock‐In (hAßKI) mouse carrying the APOE4 allele. APOE4 carriers are at increased risk for AD. Previous studies have demonstrated altered cerebrovascular integrity and function. We examined the cerebrovascular function in the hAßKI APOE4 mice at 18mo of age using perfusion‐weighted magnetic resonance imaging (PWI). We investigated brain‐wide perfusion alterations in conjunction with histopathological vessel painting.

Method

Contrast‐enhanced PWI MRI (9.4T) was undertaken from hAßKI APOE4 (n = 6) and WT (n = 5) mice at 18mo of age following tail vein cannulation for Gadolinium infusion. Imaging sequences included: T1‐pre and post‐infusion, PWI (10min) and susceptibility‐weighted imaging (SWI) for blood extravasation and iron content. All data were processed using JIM v9 software for maps of cerebral blood flow (CBF), volumes (CBV), time to peak, mean transit time and dynamic susceptibility measures for blood‐brain barrier dysfunction. Manual regions of interest (ROI) were performed for cortex, temporal lobe cortex, dorsal hippocampus and thalamus, and semi‐automatic 30+ regions based on the Allen mouse brain atlas. At the end of the in vivo experiments all mice underwent vessel painting followed by microscopic analyses.

Result

Compared to WT mice at 18mo of age, hAßKI APOE4 mice exhibited elevated CBF in virtually all regions examined. CBF was elevated approx. 16%, 11%, 4% and 23% in the cortex, hippocampus, thalamus and temporal lobe cortex, respectively. CBF was significantly elevated in the retrosplenial and temporal lobe cortices (p<0.05). CBV was also significantly increased in temporal lobe. Ongoing analyses will correlate vascular network measures (density, junctions, length) to PWI metrics as well as to hAßKI only mice.

Conclusion

The 18mo hAßKI APOE4 mouse compared to WT exhibited consistent brain‐wide elevations in cerebrovascular measures. This increase may represent a compensatory mechanism to maintain decreased metabolism that occurs with aging. The MODEL‐AD consortium (UCI/IUSM/JAX) continues to develop new and novel AD mouse models. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).
Characterization of brain metabolism, volume, and vasculature of the 5xFAD mouse model of Alzheimer’s Disease across lifespan
Authors: Jullienne Amandine , Szu Jenny , Quan Ryan , Trinh Michelle V , Norouzi Tannoz , Noarbe Brenda P , Silvola Rebecca , Bedwell Amanda A , Eldridge Kierra , Speedy Rachael , Persohn Scott C , Territo Paul R , Obenaus Andre
Published: December 2023

Background

The MODEL‐AD Consortium seeks to develop the next generation of Alzheimer’s Disease models based on human data. A popular model of familial AD is the 5xFAD mouse, characterized by early amyloid‐ß deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic features over its lifespan.

Method

Male and female 5xFAD and WT littermates underwent in vivo 18F‐FDG‐PET imaging at 4, 6, and 12 months of age to evaluate regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” that labels all cerebral vessels with a fluorescent dye. “Vessel painted” brains were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals and vessel diameter.

Result

Our analyses revealed that vessel length, vessel and junction densities increased from 4 to 12 months on the cortical surface in both 5xFAD and WT mice. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but their diameters were significantly increased only in 5xFAD mice. MCA average vessel length was decreased in 5xFAD mice compared to WT. Analysis of 18F‐FDG cortical uptake found significant interactions between WT and 5xFAD mice spanning 4‐12 months of age in retrosplenial, somatosensory and visual cortices. Broadly, 5xFAD males had increased 18F‐FDG uptake at 12 months of age compared to WT mice. In most cortical regions, female 5xFAD mice had reduced FDG uptake compared to WT across the lifespan. In males these metabolic increases coincided with decreased vessel characteristics.

Conclusion

The 5xFAD mouse exhibits AD‐like cognitive deficits with age that are associated with increasing amyloid‐ß deposition. No significant differences were found in cortical vascular features although males and females exhibited opposite effects in 18F‐FDG uptake. The MCA supplies blood to large portions of the motor cortex and increased vessel lengths and decreased collaterals along with higher metabolic rates in 5xFAD mice may be related to increasing behavioral deficits via metabolic insufficiency or other mechanisms.
Individual‐specific change in Alzheimer’s disease vulnerable brain regions across the healthy adult lifespan is associated with genetic AD risk
Authors: Roe James M , Vidal‐Piñeiro Didac , Leonardsen Esten H , Sørensen Øystein , Grydeland Håkon , Iakunchykova Olena , Walhovd Kristine B , Fjell Anders M , Wang Yunpeng
Published: December 2023

Background

Across the healthy adult lifespan, our brain’s undergo widespread structural change. Many of these changes – occurring gradually across life – are not qualitatively distinct from atrophy patterns seen in Alzheimer’s disease (AD), raising the possibility accelerated longitudinal brain change across healthy adult life may relate to genetic AD‐risk.

Method

We modelled subject‐specific structural brain change relative to that expected given age, in dense longitudinal adult lifespan data (1430 scans from 420 individuals aged 30 to 89 years; 2‐7 timepoints). Using polygenic AD scores (PRS‐AD) from four GWAS, we tested PRS‐AD associations with age‐relative change in early Braak stage regions – namely hippocampus, entorhinal cortex, amygdala, and medial temporal cortex. Next, to empirically identify features with accelerated change in AD, in ADNI data (scans = 4410; N = 978) we applied machine learning classification on the subject‐specific slopes estimated from individuals classed as consistently healthy over time versus those succumbing to AD. In healthy adult lifespan data, we then tested PRS‐AD associations with age‐relative change, in many combinations of brain features with model‐implied importance. Lastly, we tested whether high PRS‐AD individuals showing more negative brain change exhibit more longitudinal memory decline over healthy adult life.

Result

In healthy adult lifespan data, we observed many significant PRS‐AD associations with age‐relative change in hippocampus (bilateral), right entorhinal cortex, amygdala (bilateral), and left medial temporal cortex, and typically for all four scores (FDR‐corrected). We show that age‐relative change across the healthy adult lifespan in many combinations of AD‐accelerated features is significantly associated with PRS‐AD. As proof‐of‐principle, applying the ADNI‐derived model weights to the healthy adult lifespan data also enabled detection of PRS‐AD associations in healthy adults, but only using models trained on age‐relative change. Most, but not all, of the observed PRS‐AD associations were driven by APOE. Finally, we find high PRS‐AD individuals with more negative brain change exhibit significantly more memory decline, relative to high PRS‐AD individuals with less brain change.

Conclusion

The results support a dimensional account linking gradual lifespan brain changes with pathological aging, and demonstrate PRS‐AD impacts the slope of brain aging in most AD‐relevant brain regions in healthy adults.
Aβ accumulation associated with executive function decline and tau accumulation associated with memory decline in cognitively normal older people
Authors: Chen Xi , Juarez Alexis , Baker Suzanne L. , Harrison Theresa M. , Landau Susan M. , Jagust William J.
Published: December 2023

Background

The early accumulation of Aß and tau in cognitively‐normal people is predictive of future cognitive decline. It has been difficult, however, to disentangle their effects. Aß and tau target distinct regions in early stages. Frontal‐parietal regions are among the first to show Aß accumulation and are important for executive control. Temporal regions, especially the medial temporal lobe, are early sites where tau accumulates and are critical for memory. Their differential vulnerability to Aß and tau allows us to examine whether there are specific pathology‐cognitive associations, where faster decline in memory, beyond its expected level based on executive function, may be related to tau accumulation, and that faster executive function decline may be related to Aß accumulation.

Method

78 cognitively‐normal older adults from the Berkeley Aging Cohort Study underwent longitudinal 11C‐Pittsburgh compound‐B (PiB) PET, 18F‐flortaucipir (FTP) PET, and cognitive assessments of executive function and memory (Fig‐1A). We used linear mixed‐effects models to estimate longitudinal change in Aß (Fig‐1B), temporal tau (Fig‐1C), executive function (Fig‐1D), and memory (Fig‐1E). We focused on within‐individual variability in cognitive decline in different domains and computed two cognitive decline residual scores (executive function controlling for memory, Fig‐2A; memory controlling for executive function, Fig‐2B) to represent domain‐specific performance decline.

Result

Aß accumulation across wide‐spread regions, especially frontal/parietal cortex, was associated with faster executive function decline, but not memory, even after controlling for meta‐temporal tau change (Fig‐3A). On the other hand, temporal tau accumulation, especially in the medial temporal regions, was related to faster memory decline, but not executive function, even after controlling for global Aß change (Fig‐3B). Using raw cognitive slopes, instead of residual scores, yielded stronger associations with both pathologies but reduced the ability to detect specific pathology‐cognition relationships.

Conclusion

We found evidence supporting specific associations between accumulating pathology and domain‐specific cognitive decline. The “Aß‐executive function, tau‐memory” association may reflect specific vulnerabilities in the executive control network and the memory network to different pathology, leading to cognitive decline in different domains. The variability of cognitive decline within the same individual across different domains provides unique information and may be used as behavioral markers for specific pathology.
A CenTauR scale based on 18F‐MK6240
Authors: Dore Vincent , Bourgeat Pierrick , Leuzy Antoine , Huang Kun , Krishnadas Natasha , Feizpour Azadeh , Fripp Jurgen , Villemagne Victor L , Rowe Christopher C
Published: December 2023

Background

A standardized scale for the quantification of tau PET imaging would allow comparison and combination of data across tracers and sites resulting in large meta‐analysis and the application of universal cut‐offs. The proposed approach called CenTauR (CTR) was evaluated on 18F‐MK6240 using both global and regional anchoring.

Method

375 18F‐MK6240 PET & T1w scan pairs (HC Aß‐ = 179/MCI Aß+ = 98/AD Aß+ = 98) from AIBL&ADNeT were spatially normalised using SPM8 and SUVR normalised using the cerebellar cortex. PET scans were then quantified in 4 composite ROIs [Mesial‐Temporal (Me), Meta‐Temporal (MT), Temporo‐Parietal (TP) and Frontal (FT)] from a previously defined “universal” cortical mask. To anchor the 0 and 100 CTR, we only included HC Aß‐ (<10CL) and AD Aß+ (>25CL) individuals younger than 75y, with MMSE = 20, we also excluded HC participants with a quantification higher than the 75%tile in the Me and AD patients with a quantification lower than the 25%tile in the MT, resulting in 68 HC Aß‐ and 29 AD Aß+. We investigated two CTR scaling approaches using either a single transform based on the TP anchors to transform SUVR into CTR for all composites or using region‐based equations scaled with regional anchors.

Result

The mean and standard deviation (std) for the HC and AD groups are reported in Table 1. Using a single transformation resulted in the following equation: Ct = 100x(SUVR‐0.97)/2.26 Region‐based equations can be extrapolated from Table 1. Figures 1 and 2 show that regional CTR overstretches quantification in FT compared to single equation‐derived CTR. Thresholds set at 2 std above the HC were 2.38, 9.43, 7.66, 1.82, and 6.16 CTR for Me, MT, TP, FT and Global respectively, and were 7.05, 7.48, 7.66, 10.20, 7.68 CTR when using regional equation‐derived CTR.

Conclusion

The region‐based approach provided slightly more consistent CTR distributions in the HC across the ROIs however, this approach tends to over‐stretch the CTR values in the frontal region.
QyPredict prognostic model enriches selection for faster decliners in mild cognitive impairment
Authors: Gordon Elizabeth , Samper‐González Jorge , Villa Luca , Jubault Thomas , Guizard Nicolas
Published: December 2023

Background

The suboptimal selection of patients is a key challenge for disease‐modifying trials in mild cognitive impairment (MCI) and Alzheimer’s disease. Improved selection strategies are urgently needed to better power trials. Recent advances in AI predictive modeling, such as the QyPredict® algorithm, are promising tools to improve the selection of patients likely to clinically progress during the clinical trial timeframe.

Method

QyPredict® was applied to 519 MCI patients from ADNI: age: (71.8(±7.1), 303 Male, MMSE range 24‐30, CDR = 0.5, with available amyloid and APOE‐e4 + status. QyPredict®, a tunable machine learning model, incorporated baseline QyScore® volumetric MRI results, demographic (age and sex) and clinical (MMSE and CDR) inputs. A QyPredict® score (0‐1) was produced for each individual, representing the probability they will demonstrate a modelled outcome (here an increase in CDR‐SOB of 0.5+ over 24 months). A score close to zero indicating very low probability of change. Predictive performance was evaluated using positive predictive value (PPV), sensitivity and specificity. Mean and standard deviation for change in CDR‐SOB over 24 months were calculated and compared using Mann‐Whitney test at increasing QyPredict® cut‐offs (0.1, 0.2, 0.3, 0.4 and 0.5). Actual change versus predicted change in CDR‐SB scores was further investigates for ‘Stable’ (QyPredict®<0.5) versus ‘Decliners’ (QyPredict®>0.5) (Figure 1). Sample sizes to detect a 30% treatment effect (reduction in change in CDR‐SOB) were calculated for the full sample and a cohort enriched with only ‘Decliners’.

Result

For the full sample without QyPredict® enrichment, change in CDR‐SOB at 24 months was 2.3 (±2.11), which significantly increase (p<0.001) from a QyPredict®>0.2, reaching a change of 3.4 (±2.30) points for MCI patients with QyPredict®>0.5. PPV, sensitivity and specificity were: 0.76, 0.70 and 0.75 (the full cohort); 0.83, 0.77 and 0.70 (Amyloid positive patients) and 0.82, 0.75 and 0.74 (APOE‐e4 + patients). Sample sizes for a putative trial where 304 (full sample) compared with 110 (enriched cohort) per treatment arm.

Conclusion

Using baseline QyScore® metrics, basic demographic, and typical clinical data available at screening visits, QyPredict® accurately modelled the likelihood of future clinical decline, resulting in substantially reduced patient cohorts to detect treatment effects when enriched with ‘decliners’.
Microstructural integrity and structural connectivity of medial temporal lobe subregions is related to Alzheimer’s pathology
Authors: Adams Jenna N. , Granger Steven J. , Taylor Lisa M. , Kim Soyun , Harrison Theresa M. , Harris Alyssa L. , McMillan Liv , Colon‐Perez Luis , Keator David B. , Yassa Michael A.
Published: December 2023

Background

The earliest effects of Alzheimer’s disease pathology on medial temporal lobe (MTL) gray matter microstructure and white matter connectivity are still unknown. Here, we applied ultra‐high‐resolution diffusion MRI to characterize microstructural integrity and structural connectivity of the MTL, and tested associations with Alzheimer’s pathology and memory performance in cognitively normal older adults.

Method

83 participants (M = 71.7yrs, 66% female) received structural and ultra‐high‐resolution diffusion MRI (0.67×0.67×3mm). Subsamples received [18F]‐florbetapir (FBP) to measure Aß (n = 77; global summary SUVR), [18F]‐MK6240 to measure tau (n = 23; entorhinal SUVR), and performed an object mnemonic discrimination task (n = 74). Structural MRI was processed with ASHS to obtain MTL ROIs (Fig1). Diffusion MRI was processed with FSL DTIfit to calculate mean diffusivity (MD), an index of cellular integrity. Tractography was performed with DSI Studio. ROI‐to‐ROI streamlines were calculated (Fig3A) and used for structural connectivity graph analyses of the MTL network. Analyses controlled for age and sex, with scan interval and education in relevant models.

Result

Entorhinal MK6240 SUVR was associated with increased MD in transentorhinal cortex (BA35; r = 0.72, p<0.001), entorhinal cortex (EC; r = 0.61, p = 0.004), and dentate gyrus (DG; r = 0.46, p = 0.04; Fig2A), while global FBP SUVR was associated with higher MD in EC (r = 0.25, p = 0.03). Worse mnemonic discrimination performance was associated with increased MD in DG (r = ‐0.29, p = 0.01), with trends in EC (r = ‐0.23, p = 0.06) and CA3 (r = ‐0.20, p = 0.09; Fig2B). The number of streamlines between EC and DG was not significantly associated with entorhinal MK6240 SUVR (r = ‐0.32, p = 0.17), FBP SUVR, or mnemonic discrimination (ps>0.37). Lower global efficiency of the MTL network was associated with increased entorhinal MK6240 SUVR (r = ‐0.50, p = 0.025) yet better mnemonic discrimination performance (r = ‐0.28, p = 0.02; Fig3B).

Conclusion

Entorhinal tau pathology and memory performance are closely related to microstructural integrity and structural connectivity of the MTL, suggesting tau‐related MTL neurodegeneration may drive early memory decline.