bluuebunny/crossref_metadata_2025 huggingface dataset:
The association between measures of subjective cognitive decline and Alzheimer’s disease plasma biomarkers in cognitively normal individuals
Authors: Bernard Mark A , Boutajangout Allal , Debure Ludovic , Briggs Anthony Q , Vedvyas Alok , Marsh Karyn , Osorio Ricardo , Shao Yongzhao , Betensky Rebecca A , Wisniewski Thomas , Masurkar Arjun V.
Published: January 2025

Background

Subjective cognitive decline (SCD) is thought to be a preclinical stage of Alzheimer’s disease (AD), associated with faster disease progression and with imaging and cerebrospinal fluid biomarkers. However, it is unclear whether and how the degree of SCD correlates with plasma biomarkers. To address this, we investigated the association of plasma biomarkers of AD with established validated measures of SCD.

Method

The study included 122 cognitively normal older adults (age ≥60 years, 72 non‐Hispanic White, 50 Black/African American) evaluated at the NYU Alzheimer’s Disease Research Center. Participants underwent a comprehensive battery of psychometric tests according to NACC UDS 3 standards. Degree of SCD was quantified using the Brief Cognitive Rating Scale (BCRS) and Cognitive Change Index (CCI). Plasma levels of Aβ40, Aβ42, total tau, ptau‐181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured using ultra‐sensitive, single‐molecule array (SIMOA) technology. Secondarily‐calculated measures included Aβ42/Aβ40, tau/Aβ42, and ptau‐181/Aβ42 ratios. Linear regression (models unadjusted and adjusted for age) was used to evaluate the strength of association between psychometric measures and plasma biomarkers.

Result

In unadjusted linear regression, both higher BCRS (β = .0420, r2 = .1135, F = 7.682, p = .0074) and CCI (β = .0059, r2 = .1636, F = 11.732, p = .0011), each indicative of a higher degree of SCD in this cognitively normal population, were found to be predictive of higher plasma tau/Aβ42 ratio. In age‐adjusted models, higher BCRS (β = .0368 p = .0087) and CCI (β = .0066, p = .0019) remained significantly predictive of higher plasma tau/Aβ42, with higher CCI additionally found to be predictive of lower plasma Aβ40 (β = ‐1.659, p = .0210). Statistically significant associations of SCD measures were not observed with Aβ42/Aβ40, ptau‐181/Aβ42, NfL, or GFAP.

Conclusion

Validated measures of SCD significantly associated with tau/Aβ42 ratio and Aβ40 levels in plasma, but do not show significant association with other biomarkers. This suggests that the degree of SCD in cognitively normal individuals could potentially signify early aspects of neurodegeneration that are distinct from other pathways. This relationship warrants further study in longitudinal studies of SCD cohorts.
Gradient Analysis for the Study of Alzheimer’s Disease
Authors: Camargo Aldo , Wang Ze
Published: January 2025

Background

Dys‐connectivity has been repeatedly shown in Alzheimer’s Disease (AD) but the change of connectivity gradient across the brain is under‐studied. In this study, we used resting state fMRI (rsfMRI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to build a whole brain functional connectivity matrix. We then compared the major connectivity gradients decomposed from the connectivity matrix from normal controls (NC), mild cognitive impairment (MCI), and AD patients.

Method

30 NC, 11 MCI, and 40 AD were included in the analysis. Data preprocessing including motion correction, slice time correction, normalization, and artifact component removal, was performed using SPM12 and FSL. Mean rsfMRI time series was extracted from each of the 400 segments in the Schaefer atlas. A 400×400 functional connectivity matrix was calculated for each subject. Connectivity gradients were subsequently calculated using the BrainSpace toolbox. A mean connectivity matrix and its gradients were calculated for NC, MCI, and AD separately. Individual subject’s gradients were then aligned to those population level ones and compared across groups through two‐sample t‐test. Our analysis limits to the first three gradients as the corresponding eigenvalues explained >39% of the original matrix variance. Multiple comparison correction was performed using Bonferroni correction.

Result

Fig. 1 shows the first gradient map for each sub‐group. The gradients were lowest in occipital cortex, and increased in the motor network and temporal cortex, and then gradually went down toward prefrontal cortex. Fig. 2‐4 are the statistical comparison results. The first gradient map showed the largest cross‐sectional changes. Compared to NC, MCI had reduced gradients in occipital cortex, motor cortex, and temporal cortex. Gradients in occipital cortex and posterior part of temporal cortex further reduced in AD compared to MCI, and AD patient showed gradient reduction in prefrontal cortex.

Conclusion

We found consistent functional connectivity gradient reduction in the AD continuum in occipital cortex and temporal cortex, suggesting a common pathway of AD‐related impairment to functional connectivity. Gradient reduction was identified in motor cortex in MCI compared to NC and was found in prefrontal cortex in AD compared to MCI, likely related to the escalated cognitive control and working memory decline in AD.
The relationship between right and left hemisphere regional tau and proper name recall from Logical Memory story recall
Authors: Olson Hayley A , Langhough Rebecca E. , Bruno Davide , Hermann Bruce P , Basche Kristin E , Miess Beryl , Kaminski Noelle , Mandel Olivia , Christian Bradley T. , Johnson Sterling C. , Betthauser Tobey J. , Mueller Kimberly D
Published: January 2025

Background

Sensitive screening for early Alzheimer’s disease (AD)‐related cognitive decline are needed. Prior research links high beta‐amyloid (Aß) levels to reduced proper name (PN) retrieval in individuals without cognitive impairment. We examined whether language‐related regional tau from PET associated with Logical Memory (LM) proper name recall, accounting for LM covariates.

Method

Participants included n=396 from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) with Logical Memory (LM) story recall, amyloid PET ([11C]Pittsburgh Compound‐B, PiB), and [18F]‐MK‐6240 tau PET; all were unimpaired at LM baseline. Outcomes included z‐scores for LM delayed total score (“total‐LM”) and PN delayed LM subscore (“PN‐score”) from the visit most adjacent to PET‐tau imaging. Amyloid PET burden (visit adjacent to tau PET) was summarized as a global PIB DVR (PiB index, cerebellum GM reference region, graphical analysis). Left and right volume‐weighted MK‐6240 SUVR (inferior cerebellar GM reference regions) averages were calculated for regions previously associated with PN retrieval, including temporal pole, anterior temporal gyrus, anterior middle gyrus, and anterior inferior gyrus (“PN‐regional‐tau‐network”). We compared results from two ANCOVA models (L vs. R regional network as predictors) for each outcome (PN‐score, total‐LM). Covariates in each model included age at LM, sex, WRAT‐3 reading, and PiB index (to replicate prior analyses). To account for unexplained variance from global tau in entorhinal cortex, residuals from a regression of global tau on PN‐regional‐tau‐network were also included.

Result

Table 1 displays demographics overall and by tau status (T+/T‐). Overall mean age was 67 (SD=7); n(%)=80(20.2%) were T+. Left and right PN‐regional‐tau‐networks were significant predictors of PN‐score (ß=‐.06, R2=.190, ß=‐.08, R2=.192, respectively) and total‐LM (ß=‐.08, R2=.201, ß=‐.09, R2=.202, respectively; Table 2, Figure 1). In sensitivity analyses removing n=23 participants with MCI or dementia, Right‐hemisphere PN‐regional‐tau (but not left) was still a significant predictor of PN‐score (ß=‐.06, R2=.190), and L and R PN‐regional‐tau significantly predicted total‐LM (ß=‐.06, R2=.134, ß=‐.07, R2=.136, respectively).

Conclusion

Logical Memory story recall measures may be sensitive to tau burden in specific language regions; right hemisphere tau in the PN‐regional‐network may be particularly sensitive to early tau burden. Future directions include characterizing regional PET patterns and plasma‐biomarker‐related preclinical rates of change in these outcomes.
Genetic predisposition to clinical AD and AD pathology is differentially associated with baseline and 3‐year period change for specific AD‐related markers
Authors: Genius Patricia , Rodríguez‐Fernández Blanca , Shekari Mahnaz , Sánchez‐Benavides Gonzalo , López‐Martos David , Minguillon Carolina , Esteller Manel , Navarro Arcadi , Gispert Juan Domingo , Vilor‐Tejedor Natalia
Published: January 2025

Background

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by early changes in brain structure and cognitive function before the age of onset. This study investigated whether the genetic load for clinical AD and AD pathology predicts AD‐related brain and cognitive changes over a 3‐year period, targeting the preclinical phase in cognitively unimpaired (CU) middle‐aged individuals.

Method

The sample of the study was defined by 429 CU middle‐aged participants at risk of AD from the ALFA+ nested cohort with available information on genetics, brain imaging markers and cognitive data [Table 1]. A subset of them had information at two‐time points (N = 367) [Figure 1]. Genetic predisposition for clinical AD (PRSAD and PRSADnoAPOE) and AD pathology (PRSAβ42‐CSF and PRSpTau‐CSF) were calculated. We used linear regression models to assess the association between each PRS and global amyloid PET deposition expressed in Centiloids, AD Dickerson MRI‐signature, hippocampal volume and cognitive outcomes, at baseline and rate of change over visits after controlling for confounders. PET and MRI outcomes were defined as the annual rate of change. Cognitive outcomes were z‐scores of the two‐time points difference. Models were adjusted for time between visits.

Result

At baseline, higher genetic predisposition to clinical AD was associated with increased amyloid‐PET levels and higher average thickness of AD‐affected regions. Additionally, higher PRSAD was associated with reduced AD‐related cognitive performance and worse language [Figure 2]. Over the three‐year period, AD‐genetic load predicted higher annual amyloid accumulation in the brain, independently of APOE. Conversely, genetic predisposition to higher CSF Aβ42 levels predicted lower annual rate of change for Centiloids. PRSAD was also associated with annual reduction of hippocampal volume. Finally, genetic predisposition to AD beyond the APOE region was associated with executive functioning rate of change[Figure 2].

Conclusion

The results of this study showed the role of genetic predisposition to AD, affecting amyloid PET deposition, brain structure changes, and cognitive decline. These findings emphasized the importance of considering a comprehensive range of genetic markers in risk assessments for AD, particularly in its early stages, and highlight the potential of personalized genetic approaches to enhance predictions and interventions in the management of AD.
Influence of tau pathology and anxiety and depressive symptoms on metamemory in cognitively normal older adults
Authors: Crawford Jennifer L. , Adornato Alex , Matulonis Johanna , Hooker Jacob M. , Berry Anne S.
Published: January 2025

Background

The ability to accurately discern memory function (i.e., metamemory) decreases with age and is further diminished in Alzheimer’s disease (AD). As such, changes in metamemory may be a sensitive behavioral indicator of pre‐symptomatic AD.

Method

Cognitively normal older adult participants (N = 48) completed a neuropsychological battery consisting of episodic memory tasks (California Verbal Learning Task, Face‐Name Associative Memory Exam) and self‐reported measures of metamemory (Multifactorial Memory Questionnaire) and anxiety and depressive symptoms (Geriatric Depression Scale, Penn State Worry Questionnaire, Mood and Anxiety Symptom Questionnaire). Z‐scores from each measure were combined into three separate composite scores: memory ability, metamemory, and anxiety and depressive symptoms. All participants also had a tau PET scan ([18F]MK‐6240) completed within 12.7 (SD = 11.6) months of neuropsychological testing in which standardized uptake value ratios (SUVR) referenced to the inferior cerebellar gray matter were calculated using Freesurfer‐defined ROIs for Braak I, Braak II, metatemporal, and amygdala regions of interest (ROIs). Linear regression models were used to test for the contribution of anxiety and depression symptoms, tau pathology, and memory ability on metamemory; education, age, and sex were entered as covariates in all models.

Result

Behavioral analyses suggest that anxiety and depression symptoms (t = ‐2.1, p = 0.046), but not memory ability (t = 0.4, p = 0.698), were related to metamemory. Interestingly, tau pathology helped to explain additional variance in the relationship between metamemory and anxiety and depressive symptoms. Specifically, amygdala tau interacted with anxiety and depression symptoms to predict metamemory (t = ‐2.61, p = 0.013), when controlling for age, sex, education, and memory ability, such that participants with both high levels of anxiety and depressive symptoms and high levels of amygdala tau pathology had lower self‐reported metamemory (Figure 1). This relationship was not observed in Braak I, Braak II, or metatemporal ROIs (ps > 0.07).

Conclusion

Together, these results suggest that depressive and anxiety symptoms are an important metric to consider when examining the relationships between tau pathology and metamemory. Further, the results underscore that mechanisms supporting metamemory are likely distinct from those underlying memory ability and each merit unique consideration towards understanding their relationship to AD pathology.
Multivariate analysis of white matter crossing fibers reveals correlations with aMCI and dementia diagnoses
Authors: Bender Andrew R. , Weissman Caleb , Scheel Norman , Jung Youjin , Damoiseaux Jessica S. , Peltier Scott J , Hampstead Benjamin M.
Published: January 2025

Background

Diffusion magnetic resonance imaging (dMRI) permits characterizing differences in white matter microstructure associated with amnestic mild cognitive impairment (aMCI) and Alzheimer’s dementia (AD). However, most dMRI measures aggregate signals across multiple axonal fiber populations with varying spatial orientations, which limits the sensitivity and specificity of clinical diagnosis. To overcome this shortcoming, we estimated fiber density (FD) measures, independently from crossing fiber populations, and extracellular cerebral spinal fluid (CSF). We hypothesized that aMCI and AD diagnoses are associated with differential patterns of FD changes in larger and smaller diameter fiber populations.

Method

We evaluated cross‐sectional dMRI data from 179 clinically characterized participants enrolled in the University of Michigan Memory and Aging Project. Image processing leveraged the MRtrix3 multi‐shell multi‐tissue fixel‐based analysis framework to estimate FD, separately for three fiber orientations, and CSF. Data analysis used multi‐block partial least squares correlation (PLS‐C) to estimate factors from multidirectional FD and CSF images correlated with differences between cognitively unimpaired (CU; n = 98) and those diagnosed with aMCI (n = 52) or AD (n = 29).

Result

The PLS‐C model yielded three significant latent variables (LVs; Fig. 1), reflecting patterns of both significant positive and negative associations between diagnosis and FD in crossing fibers. LV1 explained 80% of the differences from CU to aMCI to AD, demonstrating a stepwise reduction of FD and increased CSF with greater disease severity. However, LV2 and LV3 showed FD differences in smaller crossing fibers, distinguishing clinical diagnoses. Intriguingly, participants in the aMCI and AD groups showed different regions with increased or decreased FD in smaller crossing fibers, relative to CU participants. Pairwise PLS‐C models showed aMCI and AD diagnoses were associated with similar patterns of FD changes in smaller crossing fibers in overlapping regions.

Conclusion

The present study found distinctive patterns of white matter alterations that systematically differ across diagnostic severity in MCI and Alzheimer’s dementia. These results highlight the value of decomposing signals from crossing fibers as a sensitive neuroimaging correlate to clinical diagnosis. These findings challenge the common perspective that MCI and Alzheimer’s dementia are associated with monotonic declines in white matter integrity.
Novel MRI method enables in vivo quantification of pre‐atrophic neurodegeneration in a mouse model of Alzheimer's Disease
Authors: Tomaszewski Michal R , Sukstansky Alexander L , Haley Hyking D , Meng Xiangjun , Miller Corin O , Yablonskiy Dmitriy A.
Published: January 2025

Background

Robust methods are needed for preclinical evaluation of novel Alzheimer Disease (AD) therapies to accelerate drug discovery. Quantitative Gradient Recalled Echo (qGRE) MRI shows significant promise to provide insight into neurodegeneration in AD prior to atrophy development in humans, with qGRE R2t* metric (tissue‐specific subcomponent of R2*) highlighting areas of low neuronal density (doi:10.3233/JAD‐210503). In this study a novel qGRE method is shown to non‐invasively measure the longitudinal neuronal loss in the hippocampus of a mouse model of AD tauopathy Tg4510.

Method

Tg4510 (n=15) and wild type (WT, n=7) mice underwent MRI (7T field strength) at 3, 5, 6, 7 months old (WT at 3 and 5mo only). Mice were isoflurane‐anesthetized to minimize BOLD contribution to R2* signal. 3D Multi‐GRE sequence was used to generate R2* maps. Light‐sheet microscopy of the brains stained with NeuN and MBP was used to visualize neuronal nuclei and myelin content respectively.

Result

Significant decrease in NeuN staining between 3mo and 6mo was observed in the hippocampus of Tg4510, indicating a decrease of over 30% in neuronal density (p<0.001, Figure 1), validating the mouse model. Longitudinal analysis showed clear changes in R2* values in the Tg4510 hippocampus undergoing neurodegeneration between 3 and 5 months old (Fig. 2). Histogram analysis revealed patterns of increase in low R2* value (Dark Matter, DM), and broadening of R2* distribution. These were quantified as significant increase in both DM Volume Fraction (DMVF) and R2* Standard Deviation (SD) in Tg4510 mice (Figure 3, p=0.004/p=0.016 DMVF/SD) but not in WT controls (p>0.25). Further monotonical increase was also observed in both metrics in time. A significant negative correlation was observed between myelin content and the DMVF (p=0.01, r=‐0.76) in the hippocampus, suggesting sensitivity of the technique to the loss of myelinated axons.

Conclusion

In this study a method is proposed for using R2* relaxometry as a direct biomarker of the neuronal loss. Low R2* volume fraction (DM) and the heterogeneity of R2* both show high sensitivity for capturing longitudinal neurodegeneration. The presented technique, together with accompanying histological validation can be readily applied in preclinical models of neurodegeneration for pharmacodynamics and mechanism of action assessment.
Improved Disease Subtyping and Staging using Dual Biomarker Amyloid PET
Authors: Scott Catherine J , Coath William , Dickson John C , McQuaid Sarah J , Cash David M , Schott Jonathan M
Published: January 2025

Background

Data‐driven disease progression models of Alzheimer’s disease (AD) have identified subtypes in regional patterns of Aß deposition using amyloid PET. In addition to Aß accumulation, early frame measures of tracer delivery from amyloid PET are strongly correlated with blood flow. This work explores whether combining tracer delivery with amyloid binding measures can improve the subtype and stage characterisation over amyloid binding alone.

Methods

Data was included from participants in three studies: Insight46, a neuroimaging sub‐study of the Medical Research Council National Survey of Health and Development (n=405), AVID2, a study of patients with a differential diagnosis of Alzheimer’s Disease (n=15), and YOAD, a study of patients with clinically diagnosed young onset Alzheimer’s disease (n=15). All participants underwent a full dynamic 18F‐Florbetapir PET/MR scan. PET images were reconstructed from 0‐2 and 40‐50 minutes post injection to generate the tracer delivery and amyloid binding images, respectively. T1 parcellations were used to calculate regional standardised uptake value ratios (SUVRs) using a cerebellar grey matter reference region. Tracer delivery and amyloid binding SUVRs for 6 cortical regions were converted into z‐scores, assuming unimodal and bimodal distributions respectively, and modelled using subtype and stage inference (SuStaIn). Participants fitted as stage zero were excluded.

Results

Figure 1 shows the three subtypes found using regional amyloid binding SUVR. Subtype 2 accumulates amyloid first in the occipital lobe, while for subtypes 1 and 3, which accumulate Aß first in the precuneus and insula respectively, this is the last area to show Aß deposition. Two distinct subtypes were found with blood flow SUVR; frontal or precuneus first blood flow reduction, Figure 2. When both measures are combined, Figure 3, the data show that subtypes 1 and 2 exhibit amyloid accumulation before blood flow changes, whereas subtype 3 shows blood flow changes in all regions first. The two blood flow subtypes are spread across all three combined subtypes, suggesting that each amyloid subtype may have several blood flow subtypes.

Conclusions

Combining blood flow and amyloid SUVR within SuStaIn reveals new patterns of disease progression compared to amyloid alone. This may help us better understand heterogeneity in aging and disease.
Neurobiological and clinical characteristics of amnestic patients with Lewy body pathology
Authors: Silva‐Rodríguez Jesús , Moscoso Alexis , Labrador‐Espinosa Miguel , Sanchez‐Juan Pascual , Schöll Michael , Grothe Michel J.
Published: January 2025

Background

While Lewy body (LB) pathology typically associates with a distinct clinical profile compared to Alzheimer’s disease (AD), early memory deficits are not uncommon and can confound clinical diagnosis of amnestic patients. Moreover, approximately 30‐60% of AD patients have concomitant LB pathology, which has been reported to affect the clinical phenotype and result in a more aggressive disease course. Recently developed a‐synuclein seed amplification assays (aSyn‐SAAs) have demonstrated high diagnostic accuracy for LB diseases, but the role of these novel biomarkers in the context of amnestic presentations typical for AD remains to be investigated in more detail.

Method

We studied 872 patients from the ADNI cohort with a baseline diagnosis of aMCI (N=661) or AD dementia (N=211), who had CSF and FDG‐PET data available. CSF samples were analyzed for peptide levels of Aß1‐42 and p‐tau181, and aSyn positivity was evaluated using a novel aSyn‐SAA. Based on positive/negative results on the different biomarkers, subjects were grouped into “AD‐/LB‐” (A‐T‐aSyn‐, N=106), “AD+/LB‐” (A+T+aSyn‐, N=336), “AD+/LB+” (A+T+aSyn+, N=158) and “AD‐/LB+” ((A‐|T‐)aSyn+, N=68). We analyzed group differences in demographics, APOE4 positivity, neurodegeneration patterns (FDG‐PET), as well as baseline and longitudinal scores of global cognition (MMSE) and domain‐specific function (ADNI_MEM, ADNI_EXEC).

Result

At baseline, AD+/LB+ showed worse global cognition (MMSE: d=‐0.27, p=0.004) and memory performance than AD+/LB‐ (ADNI_MEM: d=‐0.26, p<0.006). AD‐/LB+ were less globally impaired (p<0.001) and characterized by a markedly more dysexecutive profile (d(MEM‐EXEC): p<0.002). AD+/LB+ progressed faster on all cognitive scores, but they did not develop a differential cognitive profile compared to AD+/LB‐ (Figure 1). APOE4 positivity was similar between AD+/LB+ and AD+/LB‐ (72% vs. 75%, p=0.28) but lower in AD‐/LB+ (28%, p<0.001). In FDG‐PET, AD+/LB+ was characterized by a temporo‐parietal hypometabolism pattern similar to that of AD+/LB‐ but with higher effect sizes (Fig‐2). By contrast, AD‐/LB+ showed a strikingly different posterior‐occipital pattern of hypometabolism.

Conclusion

LB co‐pathology in AD was associated with more severe neurodegeneration and faster cognitive decline, but an amnestic AD‐typical phenotype. By contrast, patients with relatively pure LB pathology were characterized by a more dysexecutive cognitive profile and a distinct hypometabolism pattern typically suggestive of LB disease.
Metabolic glutamate receptor 5 (mGluR5) is associated with tau pathology in mild Alzheimer's disease
Authors: Wang Yan , Xie Fang , Guan Yihui
Published: January 2025

Background

Alzheimer's disease (AD) is characterized by the deposition of amyloid plaques and tau neurofibrillary tangles in the brain with continuous cognitive impairment. Although the mechanism underlying AD pathogenesis remains unclear, more evidence suggests that synaptic dysfunction and loss may be an early event in disease progression. Metabotropic glutamate receptor 5 (mGluR5), a kind of G protein–coupled receptor, is involved in AD pathology through modulating synaptic transmission and plasticity and thus exhibits therapeutic effects. However, research on the associations of mGluR5 with the neuropathological hallmarks of AD needs to be completed.

Method

In this single‐center, cross‐sectional study, fifteen patients with mild AD and thirteen normal controls (CN) underwent a PET/MRI scan with [18F] PSS232 (mGluR5 availability) and trouble PET/CT scan with [18F] florbetapir (ß‐amyloid) and [18F] MK6240 (tau deposition). The associations of [18F] PSS232 and [18F] MK6240 binding were investigated. We also investigated the correlations of tau deposition and mGluR5 availability with cognitive performance. Voxel‐wise and volume‐of‐interest (VOI) analyses were performed on PET data.

Result

Compared to CN, individuals with mild AD showed smaller clusters of [18F] PSS232 binding in the hippocampus and increased tau deposition in the hippocampus, lateral temporal, posterior cingulate, frontal, occipital, and parietal (Figure 1). Based on Voxel‐wise and VOI analyses, tau deposition in the hippocampus was negatively associated with [18F] PSS232 binding in the hippocampus (r = 0.56, p = 0.002, Figure 2). Lower neuropsychological test scores were associated with decreased [18F] PSS232 and increased [18F] MK6240 binding in the hippocampus (Figure 3).

Conclusion

Patients with mild AD have significant reductions in mGluR5 availability and have high tau deposition in the hippocampus, which is considered the critical region involved in early cognitive impairment. That means mGluR5 and tau were interrelated in the hippocampus and may apply in tau spreading. The correlation of mGluR5 availability and tau deposition in severe AD patients and more longitudinal data are needed to illustrate the role of mGluR5 in AD pathology.
Perfusion and cerebrovascular reactivity characterization in Alzheimer’s disease and vascular dementia
Authors: Keeling Elizabeth G. , McElvogue Molly M. , Ott Lauren R. , Burke Anna D. , Sabbagh Marwan N. , Bakkar Nadine , Stokes Ashley M.
Published: January 2025

Background

Cerebrovascular changes are often reported in normal aging, Alzheimer’s disease (AD), and vascular dementia (VaD). Cerebral perfusion and cerebrovascular reactivity (CVR) both decrease with dementia compared to healthy aging; as these changes occur prior to symptomatic onset and in distinct brain regions, perfusion and CVR may act as complementary biomarkers of early cerebrovascular changes. These biomarkers can be measured using MRI methods, yielding macrovascular measures of perfusion and CVR. We recently developed a more advanced method capable of measuring microvascular‐specific measures of perfusion and CVR. Here, we characterized the cerebrovascular profiles of AD and VaD using complementary perfusion and CVR biomarkers representing both macrovascular and microvascular regimes.

Method

MRI data were acquired at 3T (Ingenia, Philips) in three cohorts: non‐cognitively impaired cohort (HC), AD, and VaD (Table 1). Perfusion data were acquired with a multi‐echo, multi‐contrast (SAGE) acquisition (5 echoes, 7.7/26/56/74/92 ms), before, during, and after injection of gadolinium‐based contrast agent. Acquisition parameters include: repetition time (TR) = 1.5 s, voxel size = 2.75×2.75×5 mm, 200 volumes, acquisition time = 5 min. SAGE functional MRI (fMRI) data were acquired in the same cohort with the same TEs and the following acquisition parameters: TR = 3.0 s, voxel size = 3 mm3, 160 volumes, acquisition time = 8 min. SAGE data underwent standard pre‐processing. Macro‐ and microvascular cerebral blood flow (CBF), relative cerebral blood volume (rCBV), and relative CVR (rCVR) were calculated using advanced analysis pipelines. The Montreal Cognitive Assessment (MoCA) was administered prior to MRI acquisition.

Result

As expected, microvascular perfusion and rCVR were lower than the corresponding macrovascular metrics for all groups. Macrovascular and microvascular CBF were lower for AD and VaD compared to HC, while there was no difference in CBF between AD and VaD (Figures 1,2). Similar trends were observed for rCBV. There were no differences in macrovascular rCVR between groups; microvascular rCVR was lower for AD and VaD compared to controls.

Conclusion

Macrovascular and microvascular perfusion decreases with AD and VaD. Enrollment is ongoing, and future directions include analysis of perfusion metrics within cortical and subcortical regions and correlation of neuroimaging findings with cognitive testing.
Cerebral Blood Flow in Midlife Obesity: Associations with Visceral and Subcutaneous Abdominal Adipose Tissue
Authors: Dolatshahi Mahsa , Commean Paul K. , Dai Weiying , Nguyen Caitlyn , Lloyd LaKisha , Kasani Sara Hosseinzadeh , Sirlin Claude , Mittendorfer Bettina , Benzinger Tammie L.S. , Ippolito Joseph E. , Morris John C. , Raji Cyrus A.
Published: January 2025

Background

Obesity and higher adiposity in midlife are recognized as contributors to Alzheimer disease (AD). Neurodegeneration in AD is at least partly mediated by vascular compromise and brain hypoperfusion. In this study, we aimed to investigate the associations between BMI and abdominal visceral and subcutaneous adipose tissue (VAT, SAT) and brain cerebral blood flow (CBF) in cognitively normal midlife individuals.

Method

A total of 66 middle‐aged cognitively normal adults (age: 49.86±5.99 years, females: 66.7%, obesity (BMI of 30 kg/m2 or higher): 51.5%, BMI: 31.72±6.96 kg/m2) underwent abdominal and brain MRI. Using an in‐house Matlab program, abdominal VAT and SAT were automatically segmented followed by manual editing. A 3D Pseudo‐Continuous Arterial Spin Labeling (pCASL) sequence, with a single post‐labeling delay of 2.025 s, was used for assessing CBF. SPM12 was used to generate ASL absolute CBF (aCBF) maps with a single compartment model, co‐registered to the gray matter segmentations, and normalized to MNI space, followed by spatial smoothing. Using AAL3 atlas and Matlab, region of interest masks were created for amygdala, hippocampus, posterior cingulate, precuneus, parahippocampal, medial orbitofrontal, and middle temporal cortices and applied to absolute CBF (aCBF) maps. The aCBF differences between the obese vs. non‐obese, high‐VAT vs. low‐VAT, and high‐SAT vs. low‐SAT was assessed, with age and sex as covariates. Also, BMI, VAT, and SAT as separate predictor variables, with age and sex as covariates, were used for voxel‐wise analysis.

Result

There was a lower whole‐brain aCBF in the high‐VAT (p = 0.004) group and obese (p = 0.005) individuals, more prominently in the left middle temporal lobe (p = 0.002). No significant difference was observed in global and regional aCBF in the high‐SAT vs. low‐SAT groups. Voxel‐wise analyses showed significantly lower aCBF in association with BMI in temporal, occipital, and frontal lobe clusters after false discovery rate correction.

Conclusion

Obesity and increased visceral abdominal fat are associated with a lower cerebral blood flow, with a more prominent decrease in the middle temporal cortex, as an AD‐signature area, in cognitively normal midlife individuals. These findings highlight the role of obesity, especially visceral obesity, in brain hypoperfusion and potentially Alzheimer disease risk, as early as midlife.
A weakly‐supervised, MRI‐guided clustering of cognitive decline: A post‐hoc analysis of the EXPEDITION‐3 clinical trial
Authors: Nallapu Bhargav Teja , Petersen Kellen K. , Demirsoy Idris , Lipton Richard B. , Davatzikos Christos , Rabin Laura , Sajjadi S. Ahmad , Ezzati Ali
Published: January 2025

Background

Alzheimer's disease exhibits heterogeneity through varied phenotypic and pathological manifestations. Here, we aimed to investigate the potential of semi‐supervised pattern classification applied to volumetric MRI data in identifying relatively homogeneous subgroups of individuals exhibiting cognitive decline (CD) throughout the study period.

Method

We used data from the placebo arm of trial of Solanezumab for mild dementia due to AD (EXPEDITION‐3 trial). Participants were classified as showing CD if there was any increase in Clinical Dementia Rating (CDR, Sum of Boxes) from baseline to the 80 weeks of follow‐up, and as stable cognition (SC) otherwise. We applied a non‐linear, semi‐supervised clustering algorithm, HYDRA, that captures subtypes within the decliner group accounting for the heterogeneous variations that are also present in the stable group. Two models with different feature‐sets were developed: model I used only baseline volumetric MRI measures, while the model II included both baseline volumetric MRI measures and longitudinal changes observed after 80 weeks.

Result

Participants were 710 individuals with longitudinal MRI and CDR measures (mean age: 72.57[±7.69] years, 60.1% Female). Models I and II each produced two distinct subgroups of CD with notable differences in their baseline MRI volumes, and different rates of change in cognitive outcomes over the course of trial (Table 1). In both the models, one of the subgroups (Slow Decliner) had significantly lower change in scores than the other (Fast Decliner) on the 11‐item version of the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS‐Cog) at the end of Week 80 (Figure 1). In Model‐I, both the decliner subgroups had smaller temporal and parietal lobe volumes at baseline compared to the Stable group (Figure 2). In Model‐II, the Slow Decliner group had higher baseline MRI volumes than the stable group and significantly lower change in ADAS‐Cog compared to that of the Fast Decliner group (Figure 2).

Conclusion

Heterogeneity in brain atrophy is linked to distinct patterns of cognitive decline. Using longitudinal changes in MRI measures revealed decliner subgroups with greater difference in ADAS‐cog scores compared to those obtained by baseline measures only.
Deletion of α5 integrin in endothelial cells ameliorates age–associated cognitive decline and increases survival in mice
Authors: Hall Gregory W , Ismael Saifudeen , Bix Gregory J
Published: January 2025

Background

Levels of inflammatory components gradually rise in tissues and blood as we age. This “inflammageing” process is often debilitating and even fatal. Cognitive impairment is one example of inflammageing’s incapacitating nature. Excessive permeation of inflammatory markers in the brain gradually erodes the blood‐brain barrier (BBB) over time. Consequently, enhanced cerebral inflammatory processes contribute to neurological senescence. Neurological inflammageing may be partly due to a5 integrin, a receptor found primarily in brain endothelial cells during brain development, cerebrovascular injury (e.g. stroke), neuroinflammation and neurodegenerative disease (e.g. ALS). We hypothesize that deletion of a5 integrin in endothelial cells helps maintain BBB integrity and leads to improved cognitive performance with age. In the past we have shown that endothelial cell selective a5 knockout (a5‐EC‐KO) mice are more resilient to ischemic stroke. Enhanced stroke recovery in a5‐EC‐KO mice is due to less a5‐related BBB deterioration and subsequently less brain edema and infiltration of peripheral inflammatory cells. Therefore, we used aged a5‐EC‐KO and wild type (WT) litter mate mice to investigate how a5 integrin influences cognitive performance and survival probability over time.

Methods

25‐32‐month‐old male and female a5‐EC‐KO mice and aged‐matched WT mice were used in the study. Cognitive function was analyzed using Y‐maze and open field. Additionally, Kaplan Meier curves were used to assess probability of survival.

Results

For Y maze, results indicate a trend towards greater alteration rate and total alteration for a5‐EC‐KO mice. Open field test shows greater center time and less peripheral time for a5‐EC‐KO. WT and a5‐EC‐KO mice have nearly identical mean speed. Additionally, Kaplan‐Meier curves indicate a greater probability of survival for a5‐EC‐KO mice between the ages of 26 to 30 months. Interestingly, 26‐30 months is the average life expectancy of a lab mouse.

Conclusions

Observations from Y maze and open field tests suggest that a5‐EC‐KO mice have improved spatial memory and less anxiety behavior when compared to aged‐matched WT mice. Moreover, the Kaplan‐Meier curves depict a greater probability of survival for aged a5‐EC‐KO mice. Thus, a5 integrin expression may significantly influence age‐related cognitive decline. Preliminary data suggests that inhibition of a5 integrin may improve symptoms of age‐associated cognitive impairment.
ApoE genotype and hippocampus have heterogenic influence on diagnosis and cognitive performance in the UCD ADRC longitudinal diversity cohort
Authors: Min Eva , Farias Sarah Tomaszewski , Johnson David K , Jin Lee‐Way , Maillard Pauline , Fletcher Evan , Whitmer Rachel A. , Decarli Charles
Published: January 2025

Background

The UCD ADRC longitudinal diversity cohort consists of individuals from diverse backgrounds including White, Black African or Hispanic/Latino Americans that vary in cognitive ability from normal to dementia. Prior studies show differences in the pathological substrate of dementia in this group1 as well as the relationship between MRI measures and cognition2. Prior work also indicates differential influence of ApoE genotype on dementia by race3. For this study, we analyzed the influence of ApoE genotype and hippocampal volume on episodic memory performance and clinical syndrome of normal (NL), mild cognitive impairment (MCI) or dementia as a group and stratified by race/ethnicity.

Method

Methods of participant recruitment and assessment for the UCD ADRC have been previously described4 Clinical syndrome was determined by a multispecialty group and coded according the UDS5. Episodic memory was measured by the SENAS6. Hippocampus was quantified using published methods7. Multivariate linear and logistic regressions were used to assess the relationships between ApoE4 genotype, diagnosis, cognition, and hippocampal volume for the entire group in addition to stratified analyses for each ethnoracial group. All analyses were adjusted for age, sex, and education (and race/ethnicity as needed).

Result

Subject characteristics are summarized in Table 1. In brief, this is a cohort diverse in race/ethnicity, cognitive ability, and educational achievement. For the entire group, odds ratios for ApoE4 prevalence were significantly higher comparing NL to MCI (1.7, p = 0.002), NL to Dementia (3.1, p <0.001) and MCI to dementia (1.7, p = 0.004). ApoE4 (Table 2) was also significantly associated with smaller hippocampus (ß = ‐0.14, p<0.001)) and poorer memory (ß = ‐0.21, p<0.001). In models where hippocampus is included, both measures are associated with episodic memory and syndrome. Different results were found for the stratified analysis where ApoE4 was not associated with syndrome or episodic memory among Blacks (Table 3). Hippocampal volume was also not associated with ApoE among Hispanic/Latinos.

Conclusion

The relationship between ApoE genotype, hippocampus, syndrome, and memory performance is variable by ethnoracial background with only White participants showing associations of ApoE with both hippocampal volume and cognition. Further evaluation is needed to understand possible causes for these differences.
A diffusion kurtosis MRI signature of subjective cognitive decline
Authors: Flaherty Ryn , Sui Yu Veronica , Li Mu , Ardelean Ana , Rusinek Henry , Masurkar Arjun V. , Lazar Mariana
Published: January 2025

Background

Diffusion weighted imaging (DWI) of brain white matter is better at predicting future cognitive decline and medial temporal lobe atrophy than cerebrospinal fluid biomarkers in subjective cognitive decline (SCD)1. However, few studies have investigated gray matter DWI in SCD, despite the importance of regional gray matter changes as a biomarker for Alzheimer’s Disease and related dementias.

Method

316 cognitively normal participants from Cam‐CAN2 (123 SCD) older than 55 were included in the analysis. Participants were placed in the SCD group if they endorsed problems with their memory. Imaging data was collected on a 3T Siemens Trio scanner2. Diffusion imaging included 0, 1000 and 2000 s/mm2 b‐values and 30 gradient directions, and were processed using MrTrix3, PyDesigner, and AMICO to apply diffusion tensor (DTI), diffusion kurtosis (DKI), and neurite orientation density and dispersion (NODDI) models. FreeSurfer with T1w and T2w images was used to segment subcortical and cortical regions (Figure 1B&C), then calculate regional volume and cortical thickness. Segmentations were also registered to diffusion images to generate regional averages of the diffusion metrics. Uncorrected p<0.05 according to Wilcoxon tests were considered significant.

Result

The metric with the most regional group differences was kurtosis fractional anisotropy (KFA) from DKI, an indicator of structural complexity. KFA was significantly lower in SCD in 17 of 84 gray matter regions, including hippocampus (Figure 2‐3B). DTI showed reduced fractional anisotropy (Figure 2‐3C) and increased mean diffusivity (Figure 2‐3D) in SCD, but for fewer regions than KFA. NODDI showed increased free water (Figure 2‐3E), increased orientation dispersion (Figure 2‐3F), and increased neurite density (Figure 3G) in SCD. Volume and thickness were higher in SCD in 5 regions, but lower in 3 regions (Figure 2‐3A). Only KFA showed group differences in hippocampus.

Conclusion

KFA was more sensitive to SCD and more consistent than regional gray matter volume, cortical thickness, and all other diffusion metrics. This may indicate KFA is a biomarker signature of SCD across the whole brain gray matter.

References:

• Selnes P, Aarsland D, Bjornerud A, et al. J Alzheimers Dis. 2013;33(3):723‐36.

• Shafto MA, Tyler LK, Dixon M, et al. BMC Neurol. 2014;14(1):1‐25.
NODDI measures of microstructural integrity in medial temporal lobe white matter pathways are associated with Alzheimer's disease pathology and cognitive outcomes
Authors: Parker Dana M , Adams Jenna N. , Kim Soyun , McMillan Liv , Yassa Michael A.
Published: January 2025

Background

Diffusion tensor imaging has traditionally been used to assess white matter (WM) integrity in Alzheimer’s disease (AD). However, the tensor model is limited in modeling complex WM structure. Neurite Orientation Dispersion and Density Imaging (NODDI), a cutting‐edge technique applied to multishell diffusion MRI, can offer more precise insights into microstructural features of WM integrity. We assessed whether NODDI more sensitively detects AD‐related changes in medial temporal lobe (MTL) WM than traditional tensor metrics.

Method

199 older adults with multishell diffusion MRI from ADNI3 (mean age = 75; 60% female; cognitively unimpaired, n=121; cognitively impaired MCI/dementia, n=78) were analyzed. Tensor metrics of fractional anisotropy (FA) and mean diffusivity (MD), as well as NODDI metrics of Neurite Density Index (NDI) and orientation dispersion Index (ODI), were calculated for MTL WM tracts (JHU Atlas: hippocampal cingulum, fornix column/body, fornix/stria terminalis, and uncinate; Figure 1). A subset of participants received 18F‐florbetapir or 18F‐florbetaben to measure Aß (n = 146; converted to Centiloids), 18F‐flortaucipir to measure tau (n=135), and neuropsychological testing including the Clinical Dementia Rating Sum of Boxes (CDR‐SB) and memory composite score (ADNI‐MEM).

Result

NODDI measures in MTL tracts were more strongly correlated with cognitive performance and AD pathology than standard tensor measures (Figure 2). For example, entorhinal tau was strongly associated with NDI in the cingulum hippocampus (r=‐0.375; p<0.001) and the uncinate (r=‐0.373; p<0.001), and with ODI in the fornix ST (r =‐0.288; p=0.004). Both ODI and NDI across the majority of tracts were associated with CDR‐SB and ADNI‐MEM (see Figure 2). In contrast, FA in any MTL tract was not significantly correlated with either tau or global amyloid‐beta, while MD in MTL tracts showed limited correlations with pathology or cognition.

Conclusion

NODDI metrics offer additional insights about MTL WM integrity in AD that were previously missed due to the limitations of DTI analyses. These results highlight the sensitivity of NODDI applied to multishell diffusion MRI acquisitions to further investigate how WM degeneration contributes to cognitive decline.
Residential Neighborhood Disadvantage and Amyloid Positivity: Findings from IDEAS
Authors: Windon Charles , Tsoy Elena , Livaudais‐Toman Jennifer , Hanna Lucy , Gatsonis Constantine , Carrillo Maria C. , Apgar Charles , Dilworth‐Anderson Peggye , Karliner Leah , Hillner Bruce E , Neilands Torsten B , Palmer Nynikka , Possin Katherine L , Stewart Anita L. , Whitmer Rachel A. , Wilkins Consuelo H. , Rabinovici Gil D.
Published: January 2025

Background

Residence in a disadvantaged neighborhood (e.g., high poverty rate, poor housing, etc.) is associated with greater dementia risk and possibly greater postmortem Alzheimer’s pathology. It remains unknown if neighborhood disadvantage is associated with in vivo beta‐amyloid positron emission tomography (PET) for Alzheimer’s. We examined this using data from the Imaging Dementia Evidence for Amyloid Scanning (IDEAS) study.

Methods

IDEAS captured >18,000 PET scans among cognitively impaired Medicare beneficiaries from 595 US dementia clinics between 2016‐2018. We defined neighborhood disadvantage using Area Deprivation Index (ADI), a validated composite of 17 social determinants measures captured in American Community Survey and US Census data. IDEAS participant zip code data was linked to census block group for ADI value calculation through geocoding. Association between visual interpretation of PET in IDEAS (positive/negative) and state‐level ADI (1‐10; 10 being greatest disadvantage) was examined via logistic regression controlling for covariates (age, sex, education, level of impairment (MCI vs dementia), race/ethnicity, comorbid conditions) with cluster adjusted standard errors by practice location.

Results

Among 13,961 cognitively impaired participants, 61.6% were amyloid positive, 56.5% had MCI, and 50.4% were female (Table 1). The majority (90.2%) were non‐Latino White with 4.7% Latino, 3.2% Black, and 1.9% Asian representation (Table 1). Participants were highly educated (68.1% beyond high school) and 31.0% (4,333/13,961) resided in neighborhoods of greater disadvantage (ADI > 6) (Figure 1). Greater ADI was associated with lower odds of amyloid positivity (aOR 0.61, 95% CI 0.51‐0.73, p<.001 for ADI 10 vs ADI 2 and aOR 0.87, 0.76‐1.00, p .051 for ADI 2 vs. ADI 1(ref)). Latino (aOR 0.62, 0.48‐0.80, p<.001), Black (aOR 0.58, 0.48‐0.72, p<.001), and Asian (aOR 0.42, 0.31‐0.58, p<.001) identity was associated with lower odds of amyloid positivity along with multiple comorbidities (Table 2).

Conclusion

We observed a relationship between residence in a more disadvantaged neighborhood (higher ADI) and lower rates of amyloid positivity. Given this finding and known association between neighborhood disadvantage and postmortem AD pathology, it is possible non‐amyloid pathology also contributes towards cognitive impairment among individuals from disadvantaged neighborhoods and among diverse groups. This has implications for clinical use of novel amyloid lowering therapies.