bluuebunny/crossref_metadata_2025 huggingface dataset:
Single cell multi‐omics implicates immune and vascular cells in Alzheimer’s etiology
Authors: Yang Andrew
Published: December 2023

Background

Understanding the genetic etiology of Alzheimer’s disease (AD) is critical to inform effective therapies but remains a challenge. Genetic heritability of late‐onset AD is ∼60‐80%, and genome‐wide association studies (GWAS) have uncovered dozens of noncoding single nucleotide polymorphisms (SNPs) that influence AD risk. Two challenges for the functional interpretation of AD genetic risk are (1) determining the cell types in which SNPs operate and (2) identifying the genes they dysregulate to drive AD pathogenesis. Single‐nucleus sequencing studies of human neurons, microglia, and other brain cell types have begun addressing these challenges. Yet, many AD risk SNPs remain unmapped. One possibility is that they are expressed in immunovascular brain cell types largely missed by current methods.

Method

Here, we optimized Vessel Isolation and Nuclei Extraction for Sequencing (VINE‐seq) to capture multimodal gene expression and chromatin accessibility assays across all major brain cell types from 30 cognitively normal, MCI, and AD human prefrontal cortex samples.

Result

We discover early gene dysregulation in immune and vascular cell types along AD progression. We highlight the gene regulatory networks mediating this dysregulation and implicate processes associated with AD pathology and cognitive decline. Finally, we map noncoding AD risk variants to diverse immune and vascular cell types, thereby expanding our understanding of AD etiology.

Conclusion

Dysfunction of diverse human brain immune and vascular cell types mediate the genetic risk for Alzheimer’s disease.
Delivery of cognition‐oriented treatments for older people with MCI in Australian Memory Clinics: A pilot implementation study
Authors: Bahar‐Fuchs Alex , Mowszowski Loren , Pike Kerryn E. , Lampit Amit , Lee Alessandra , Bentvelzen Adam , Mehrani Inga , Naismith Sharon L
Published: December 2023

Background

There is good evidence that cognition‐oriented treatments (COTs) including cognitive training and rehabilitation benefit older adults, including those with mild cognitive impairment or dementia. Despite this, there remains a research‐to‐practice gap where these interventions are not readily available in clinical practice. This paper will describe the protocol for a pilot/feasibility implementation study of rolling out COTs for people with MCI in the Australian Memory Clinic Network.

Method

The Australian Dementia Network (ADNeT) Working Group on Cognitive Interventions is tasked with bridging the evidence‐practice gap in Australian Memory Clinics. We have conducted a scoping review of COT implementation efforts around the world, a multi stakeholder survey to understand needs in gaps, have developed an online clinician‐training toolkit for choosing and delivering interventions, and are conducting an implementation study in 2023 using the RE‐AIM Implementation Framework (Glasgow et al. 2019; www.re‐aim.org), assessing Reach, Efficacy, Adoption, Implementation, and Maintenance of COTs in six participating clinics throughout Australia.

Result

Our scoping review identified 29 eligible studies but only four have used formal implementation frameworks. Cognitive stimulation was the most frequent approach in these studies, and only a small proportion investigated cost‐effectiveness and maintenance parameters. The stakeholder survey confirmed that clinicians believe it is very important to offer interventions as part of routine clinical practice, and that more training was required. Progress of our implementation study to date will be described including the clinician training tool.

Conclusion

This is the first study in Australia to address the evidence‐practice gap in COT research, and will inform the development of a larger implementation study to continue building the evidence base for the costs and benefits associated with incorporating these evidence‐based approaches in clinical practice.
Endo‐Lysosomal Dysfunction and Neuronal‐Glial Crosstalk in Niemann Pick Type C Disease
Authors: Tahirovic Sabina
Published: December 2023

Microglial activation is a neuropathological hallmark of the lysosomal storage disease Niemann‐Pick type C (NPC). Whole‐body knockout of NPC1 results in enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1‐ deficient microglia are characterized by accumulation of multivesicular bodies and impaired endo‐lysosomal trafficking of lipids while lysosomal degradation remains preserved. To study a cell‐autonomous function of NPC1 in microglia, we generated a conditional knock‐out of NPC1 in myeloid cells by crossing Npc1 flox/flox mice with Cx3cr1 +/Cre mice and characterized microglial, astrocytic and neuronal phenotypes at different pathological stages using mass spectrometry, immunohistochemistry and PET imaging. Microglial activation was the first pathological alteration detected in the brain upon loss of NPC1 in myeloid cells, reflected by altered lipidomic profiles and disease‐associated microglial signatures. Microgliosis was followed by astrogliosis as visualized by immunohistochemistry and TSPO‐ PET and Deprenyl‐D2‐PET imaging, respectively. Furthermore, the loss of microglial NPC1 resulted in neuronal injuries (axonal spheroids) and motor deficits that were detected at the age of 7 months.

Our work reveals that a specific loss of NPC1 in myeloid cells is sufficient to trigger pathology in other brain cells, suggesting that a pathological cascade initiated by microglial dysfunction may propagate to astrocytes and neurons.
Graph Theory Analysis of Structural Connectivity in Limbic‐predominant Age‐related TDP‐43 Encephalopathy Neuropathological Change (LATE‐NC)
Authors: Tazwar Mahir , Evia Arnold M , Ridwan Abdur Raquib , Bennett David A. A , Schneider Julie A , Arfanakis Konstantinos
Published: December 2023

Background

The anatomical distribution of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) typically involves the amygdala, hippocampus, and other subcortical, temporal and frontal lobe regions. But its impact on the structural integrity of this network of regions remains unknown. In this study, we tested the hypothesis that LATE‐NC is associated with abnormalities in graph theoretic measures of structural connectivity in the network of regions known to be involved in LATE‐NC.

Method

This study included 148 deceased older adults participating in Rush Memory and Aging Project and Religious Orders Study (Fig.1A). Ex‐vivo diffusion tensor imaging (DTI) scans were acquired on 3T scanners, followed by detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1B). Fractional anisotropy (FA) maps derived from DTI scans were used to define region‐to‐region structural connectivity in a network of 19 regions known to be involved in LATE‐NC using graph theory‐based network measures (Fig.2). General linear models were used to investigate the association of global and local graph measures with LATE‐NC stages, controlling for other neuropathologies (Alzheimer’s disease, Lewy bodies, arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts), demographics (age at death, sex, education), total white matter hyperintensity volume, postmortem intervals and scanner variables. Statistical significance was set at p<0.05.

Result

Linear regression revealed that greater LATE‐NC stage was associated with increased characteristic path length and with lower values of the remaining global network measures (p<0.05) (Fig.3A). LATE‐NC was also associated with lower local efficiency, increased path length, lower nodal strength, and lower clustering coefficient in 74%, 79%, 32%, and 63% of the nodes, respectively (p<0.05) (Fig.3B). Finally, LATE‐NC was associated with both greater (in 21% of nodes) and lower (in 16% of nodes) eigenvector centrality, and with both greater and lower betweenness centrality in 21% of nodes, respectively (p<0.05) (Fig.3B).

Conclusion

Using graph theory and a hypothesis‐driven approach, we found significant degradation of structural integrity in white matter of the network of regions affected by LATE‐NC. These findings may shed light on the effects of LATE‐NC on brain connectivity, and in combination with other imaging and clinical information, may aid towards the development of tools for in‐vivo detection of this devastating neuropathology.
Evaluating brain age as a marker of autosomal dominant Alzheimer disease progression
Authors: Millar Peter R , Gordon Brian A. , Benzinger Tammie L.S. , Cruchaga Carlos , Fagan Anne M. , Goate Alison , Hassenstab Jason J. , Holtzman David M. , Llibre‐Guerra Jorge J , Morris John C , Perrin Richard J. , Supnet Charlene B , Xiong Chengjie , Bateman Randall J. , Ances Beau , McDade Eric
Published: December 2023

Background

Estimates of “brain‐predicted age” quantify apparent brain age compared to normative trajectories of neuroimaging features. Brain‐predicted age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD). We used a previously‐trained model (DeepBrainNet [DBN], Bashyam et al., 2020), which requires minimal MRI pre‐processing, to predict brain age in the Dominantly Inherited Alzheimer Network (DIAN) and evaluated brain age as a marker of ADAD progression.

Method

We used DBN to predict brain age from minimally‐processed, whole‐brain T1 structural MRI scans in 265 ADAD mutation‐carriers (MCs) and 183 non‐carrier controls (NCs). We then tested whether the brain age gap (BAG; difference between predicted and true age) differed as a function of mutation and cognitive status, or estimated years until symptom onset (EYO), and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid‐ß‐42/40), phosphorylated tau (CSF and plasma pTau‐181), neurodegeneration (CSF and plasma neurofilament light [NFL]), and cognition (global neuropsychological composite and CDR‐sum of boxes). Finally, we compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of mutation variants (APP vs. PSEN1 before or after codon 200), APOE E4 carrier status, sex, and education.

Result

DBN accurately predicted age in DIAN (Figure 1A). BAG was elevated in symptomatic and asymptomatic MCs, compared to NCs, beginning around ‐10 EYO (Figure 1B,C). BAG, hippocampal volume, and a cortical thickness summary followed similar trajectories across EYO (Figure 1D). BAG was positively associated with PiB PET, CSF and plasma pTau, and CSF and plasma NFL, and was associated with worse cognitive scores, especially in symptomatic MCs (Figure 2). BAG was most elevated in MCs with a PSEN1 mutation before codon 200, but did not differ as a function of APOE, sex, or education (Figure 3).

Conclusion

We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG tracks well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, DBN‐based BAG offers unique benefits in simplicity of data processing and interpretation.
Genetic predisposition to Alzheimer’s disease is differentially associated with joint volumetric variations in the disease continuum
Authors: Genius Patricia , Calle Maria Luz , Cacciaglia Raffaele , Evans Tavia E , Falcon Carles , Minguillón Carolina , Adams Hieab H.H. , Esteller Manel , Navarro Arcadi , Gispert Juan Domingo , Vilor‐Tejedor Natalia
Published: December 2023

Background

Imaging genetics studies commonly assess the individual association between genetic information and brain features without considering joint brain modulations. The aim of this study was to explore the structural variation of the brain at different stages of Alzheimer’s disease (AD), depending on the genetic predisposition to AD.

Method

A total of 351 cognitively unimpaired (CU) middle‐age participants from the ALFA (Alzheimer’s and FAmilies) study and 330 cognitively impaired participants from ADNI (Alzheimer’s Disease Neuroimaging Initiative) with magnetic resonance imaging scans, genetic information and CSF‐amyloid status were included. They were classified as CU Aβ‐, CU Aβ+, (mild cognitive impairment) MCI Aβ+ and AD Aβ+[Table 1]. Freesurfer was used to obtain cortical and subcortical parcellations using the Desikan‐Killiany atlas. A polygenic risk score estimating each participant’s genetic predisposition to AD (PRS‐AD) was calculated including genetic variants at the genome‐wide suggestive level (5×10‐6). Individuals were classified into high/low genetic predisposition groups. Statistical analysis was based on compositional data analysis. First, we computed the optimal multivariate brain structural variation signature (elastic net selection). Then, a logistic regression was performed to determine the association between the optimal signature and the PRS‐AD. Models were stratified by disease stage and adjusted for age and sex.

Result

Individuals at different stages on the AD continuum displayed different brain volumetric modulations associated with higher genetic predisposition to AD [Figure 1]. For instance, the optimal signature associated with an increased risk of AD was mainly characterized by increased hippocampal volumes in Aβ‐ individuals, but decreased volumes in MCI individuals along with the modulation of other temporal regions. Moreover, in AD patients at higher genetic predisposition of AD, the optimal signature was characterized by increased and decreased volumes in frontal regions (e.g. pars triangularis, lateral orbitofrontal vs. medial orbitofrontal, respectively) [Figure 2].

Conclusion

Results showed AD stage‐specific multivariate volumetric variation associated with an increased genetic risk of AD. Main results suggested that regions that modulated together, although differing according to AD stage, were implicated in the structural brain topology of specific memory networks. The analysis of the joint volumetric variation of brain subregions brings an innovative modeling perspective for neurogenetic studies of AD.
Aging and Alzheimer’s Disease Have Dissociable Effects on Local and Regional Medial Temporal Lobe Connectivity
Authors: Hrybouski Stanislau , Das Sandhitsu R. , Xie Long , Wisse Laura EM , Kelley Melissa , Lane Jacqueline , Sherin Monica , DiCalogero Michael , Nasrallah Ilya M. , Detre John A. , Yushkevich Paul A. , Wolk David A.
Published: December 2023

Background

The extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional disruption of the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity (FC) alterations between anterior and posterior regions of the MTL and in MTL‐associated functional communities – the Anterior‐Temporal (AT) and Posterior‐Medial (PM) networks – in normal agers, individuals with preclinical AD, and patients with Mild Cognitive Impairment or mild dementia due to AD.

Method

In this cross‐sectional study, we analyzed data from 179 individuals from the Aging Brain Cohort study of the Penn ADRC. Detailed information about participants is provided in Table 1. For intra‐MTL FC comparisons, the MTL subregions were segmented using the automated segmentation of hippocampal subfields‐T1 (ASHS‐T1) pipeline (Fig. 1a). When modeling the MTL’s interactions with the rest of the cortex, we employed four MTL ROIs (left/right × anterior/posterior) derived from an ex vivo atlas of tau accumulation in the MTL. Our functional datasets were preprocessed using a customized fMRIprep pipeline. Sparse network estimations and modularity‐based consensus clustering were used to reconstruct the AT and PM network systems (Fig. 1b). Age effect analyses and group comparisons along the AD continuum were performed using the General Linear Model within the network‐based statistical framework.

Result

The preclinical stage of AD was characterized by increased FC between the perirhinal cortex and other regions of the MTL, as well as between the anterior MTL and its direct neighbors in the AT network (Fig. 1c‐d). This effect was not present in symptomatic AD. Instead, symptomatic patients displayed reduced hippocampal and intra‐PM connectivity. For normal aging, our results led to three main conclusions (for visuals, see Fig. 2). First, intra‐network connectivity of both the AT and PM networks decreases with age. Second, FC between the anterior and posterior segments of the MTL declines with age. Finally, within the MTL, we observed greater vulnerability of the posterior MTL subregions, particularly the parahippocampal cortex, to age‐associated FC decline.

Conclusion

Together, the current results provide evidence for aberrant connectivity in the preclinical stage of AD that may have implications for early AD pathophysiology.
Brain Volumetry‐based Amyloid PET Positivity Prediction in Subjective Cognitive Decline Patients
Authors: Jung Wooseok , Yang Dong Won , Lee Chunghwee , Hong Yun Jeong , Ho SeongHee , Jeong Jee Hyang , Park Kee Hyung , Kim SangYun , Wang Min Jeong , Choi Seong Hye , Lee Dongsoo , Kang Junghyun , Kim Jinyoung , Lee Yeha
Published: December 2023

Background

Amyloid beta PET screening for subjective cognitive decline (SCD) patients would identify a risk factor of Alzheimer’s disease (AD) at an early stage but is generally infeasible due to the high cost and radiation exposure. Brain volumetry using 3D T1 MRI integrated with genetic information can alternatively suggest amyloid positivity in SCD subjects.

Method

Individuals of age between 60 and 85 feeling cognitive decline and scoring 7% to 50% on the memory test while exceeding 7% of the other tests comprises the SCD dataset via Seoul Neuropsychological Battery (SNSB) scheme (n = 119; 26 Aß+; 24 APOE4+). We measured the volume, volume to intracranial volume ratio, cortical thickness and their normative percentiles of 104 brain subregions, respectively, using VUNO‐Med DeepBrain, an automated brain volumetry and neurodegenerative disease diagnosis‐supporting software. The significance level is set to a = 0.005 to find differentiating regions between amyloid positive and negative groups. Furthermore, four machine learning models (Logistic Regression, Random Forest, XGBoost, TabNet) were trained using the combination of APOE4 information, age, and each of the six different volumetry results to predict amyloid positivity in SCD dataset. The training dataset (n = 102; 36 Aß+; 31 APOE4+) consists of subjects from significant memory concern (SMC) cohort of ADNI2 and ADNIGO studies.

Result

Swell of the choroid plexus and shrink of the lingual cortex (both p < .005) are statistically significant in Aß+ SCD patients compared to the Ab‐ patients. The random forest model trained by the volume data plus APOE4 and age information showed the highest performance (accuracy = 0.79, AUROC = 0.75, precision = 0.81, recall = 0.79, F1 = 0.80) in the amyloid positivity prediction task among the 24 models, higher than the model without APOE4 information (accuracy = 0.70, AUROC = 0.71, precision = 0.77, recall = 0.70, F1 = 0.72).

Conclusion

The result indicates a statistically significant difference in choroid plexus volume and lingual cortex thickness between Aß+ and Aß‐ SCD patients. In addition, using both APOE e4 information and brain volumetry is crucial for amyloid positivity prediction. This study was supported by a grant from the Ministry of Health and Welfare, HI18C0530.
Intergenerational Social Mobility, Brain Structure, and Cognitive Trajectory: Findings from the Whitehall II Study
Authors: Liu Yingxu , Liu Yinghao , Cui Yuehua , Thyreau Benjamin , Zhang Ye , Taki Yasuyuki , Chen Honglei
Published: December 2023

Background

Previous studies on the effects of intergenerational social mobility on cognitive outcomes were not consistent, additionally, underlining brain anatomical variation is unclear. In the present study, we aim to examine the associations of social mobility with brain structure and cognitive trajectories in older adults.

Method

The study included 771 participants, ages 69.8 ±5.2 years, of the Whitehall II ‐ MRI substudy (2012‐2016) with data on their father’s occupation, their own occupation in mid‐life, lifestyle (smoking, drinking, physical activity, social activity, sleep disturbances, auditory difficulty, depression, obesity, hypertension), neuroimaging (T1 structural MRI) and cognitive abilities (global cognition, crystallized cognitive ability, and fluid intelligence). Social mobility was classified into stable high social class, stable low social class, upward mobility and downward mobility group based on occupational shifts from father. We used the ANCOVA tests to assess the association of social mobility with gray matter volume (GMV) and cortical thickness (CT) in various brain regions, and the growth curve modeling (GCM) to evaluate its relations to cognition over 20 years, adjusting for social lifestyle covariates and associated GMV/CT regions identified above.

Result

Social mobility was significantly related to 48 out of the 136 regions of GMV across the frontal lobe, limbic lobe, and temporal lobe; and to 4 out of the 68 regions of CT at the whole‐brain level. Stable high social class preserved the largest GMV and CT value; pair‐wise results suggest upward mobility preserved a larger GMV value than the downward mobility group (average diff. in cm3: 0.121, P<0.05); and similarly a larger CT value (average diff. in cm:0.029, P = 0.051). In GCMs, stable high social class (ref. downward mobility) had a higher entry score of fluid intelligence (b = 2.617, P<0.05), all other comparisons including the entry score and decline rate of cognitive abilities were non‐significant.

Conclusion

Our results suggest a lack of direct association between social mobility and trajectories of global cognition and crystallized cognitive ability; instead, an indirect effect through preserving the value of brain GMV and CT may occur. Additionally, an adverse causal relationship between social mobility and fluid intelligence might happen.
In vivo tau deposition in the brain stem nuclei and circadian rest‐activity rhythm change in non‐demented older adults
Authors: Jeon So Yeon , Yi Dahyun , Byun Min Soo , Jung Joon Hyung , Kong Nayeong , Chang Yoon Young , Keum Musung , Jung Gijung , Ahn Hyejin , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young
Published: December 2023

Background

Circadian rest‐activity rhythm (RAR) alterations are common in the early stage of Alzheimer’s disease (AD) disease. Given that the brainstem nuclei, the locus coeruleus (LC) and dorsal raphe nucleus (DRN) in particular, play key roles in modulating arousal and the sleep‐wake cycle, tau pathology in the brain stem nuclei, which occurs even before cortical tau progression, may relate to circadian RAR alteration in older individuals. Therefore, we aimed to test the hypothesis that in vivo tau deposition in the LC and DRN correlates with circadian RAR in non‐demented older adults.

Method

A total of 63 non‐demented older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent [11C] PiB PET and [18F] AV1451‐PET. Circadian RAR variables were measured using actigraphy for 8 consecutive days. Tau deposition of the LC and DRN (LC‐tau and DRN‐tau, respectively) was measured in the regions of interest (ROI) masks for each participant prepared in native space using the Harvard arousal network atlas for the LC and DRN. For the purpose of comparison, tau deposition in the substantia nigra (SN‐tau) was also measured in the neuromelanin sensitive MRI‐based ROI for the SN.

Result

Increased LC‐tau and DRN‐tau were significantly correlated with delayed acrophase (ß = 0.303, p = 0.024 for LC‐tau and ß = 0.398, p = 0.003 for DRN‐tau; Table 1 & Figure 1). In contrast, SN‐tau did not related with any RAR variables. Even after controlling for global tau deposition, the significance did not changed (ß = 0.321, p = 0.021 for LC‐tau and ß = 0.367, p = 0.008 for DRN‐tau, Table 1). In addition, Aß positivity showed a significant moderation effect on the relationship between LC‐tau with acrophase. Subgroup analyses showed that increased LC‐tau significantly related with delayed acrophase in Aß‐positivegroup (ß = 0.427, p = 0.004), but did not in Aß‐negative group (ß = 0.099, p = 0.615)(Figure 2)

Conclusion

Our findings support the possibility that the tau pathology in the LC and DRN underlie circadian RAR alteration, more specifically delayed phase, in non‐demented older adults. In addition, such relationship appears to be more prominent in individuals with brain Aß pathology.
Gray to White Matter Signal Ratio as a novel biomarker of neurodegeneration in Alzheimer’s disease
Authors: Putcha Deepti , Katsumi Yuta , Brickhouse Michael , Flaherty Ryn , Salat David H , Touroutoglou Alexandra , Dickerson Brad C.
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized neuropathologically by ß‐amyloid (Aß) plaques, hyperphosphorylated tau neurofibrillary tangles, and neurodegeneration which leads to a phenotypically heterogeneous cognitive‐behavioral dementia syndrome. Our understanding of how these neuropathological and neurodegeneration biomarkers relate to each other is still evolving. A relatively new approach to measuring structural brain change, gray matter to white matter signal intensity ratio (GWR), quantifies the signal contrast between these tissue compartments, and has emerged as a promising marker of AD‐related neurodegeneration. We sought to validate GWR as a novel MRI biomarker of neurodegeneration.

Method

Twenty‐nine amyloid‐, tau‐, and neurodegeneration positive patients with atypical syndromes of AD (16 Posterior Cortical Atrophy, 10 logopenic variant of Primary Progressive Aphasia, and 3 Amnestic Dysexecutive phenotype) and 24 amyloid‐negative control participants underwent structural MRI, 11C‐Pittsburgh Compound B (PiB) PET, and 18F‐flortaucipir (FTP) PET scans. Whole‐cortex vertex‐wise general linear models (GLM) were created to identify areas of the cerebral cortex where AD patients showed abnormal signal in each modality, and Pearson’s correlation coefficients were computed to examine the strength of bivariate associations between each pair of modalities at the group level. We then constructed linear mixed‐effects models to test the relative contribution of each non‐FTP modality to explaining the variance in regional FTP uptake.

Result

We found that GWR was associated with cortical thickness, tau PET, and amyloid PET, with GWR showing a larger magnitude of abnormality than cortical thickness. We also found that combining GWR, cortical thickness, and amyloid PET better explained observed tau PET signal than using these modalities alone, suggesting that the three imaging biomarkers contribute independently and synergistically to explaining the variance in the distribution of tau pathology.

Conclusion

We conclude that GWR is a uniquely sensitive in vivo marker of neurodegenerative change that reflects pathological mechanisms which may occur prior to cortical atrophy. By using all of these imaging biomarkers of AD together, we may be better able to capture, and possibly predict, AD neuropathologic changes in vivo, which we hope will ultimately contribute to better endpoints to evaluate the efficacy of therapeutic interventions as we move toward an era of disease‐modifying treatments for this devastating disease.
Social engagement, amyloid burden, and dementia: the Atherosclerosis Risk in Communities (ARIC)‐PET study
Authors: Groechel Renée C. , Liu Chelsea , Knopman David S. , Koton Silvia , Kucharska‐Newton Anna M. , Liu Albert C. , Lutsey Pamela L. , Mosley Thomas H. , Palta Priya , Sharrett Richey , Walker Keenan A. , Wong Dean F. , Gottesman Rebecca F.
Published: December 2023

Background

Although amyloid deposition in the brain is often associated with subsequent dementia risk, not everyone with brain amyloid will develop dementia. This discrepancy illustrates the potential importance that risk factors and lived experiences may have in modifying this association. Compared to participants with low social engagement (SE) in mid‐life, we hypothesized that participants with high mid‐life SE will show a weaker association between amyloid burden and incident dementia.

Method

We included data from 310 non‐demented participants of the Atherosclerosis Risk in Communities (ARIC)‐PET study. Social support and isolation were assessed via interviewer‐administered questionnaires (Visit 2; 1990 – 1992). Based upon categorization of both factors, participants were classified as having high, intermediate, or low mid‐life SE (Table 1). Brain amyloid was evaluated with florbetapir PET (Visit 5; 2011‐2014). Elevated amyloid burden was defined as standardized uptake value ratio (SUVR) >1.2 in the global cortex. Incident dementia cases were identified from visit 5 through 2019 through ongoing surveillance utilizing in‐person neurocognitive testing, informant interviews, and hospitalization codes. Relative contributions of mid‐life SE and elevated florbetapir SUVR to incident dementia, independently and with multiplicative interaction terms, were evaluated with Cox regression models, adjusted for demographics, APOEe4 and vascular risk factors

Result

Among 310 participants, 48 developed dementia (median follow‐up: 4.7 years). Mid‐life SE and elevated SUVR each independently predicted dementia risk but did not interact on a multiplicative scale. Participants with high or intermediate mid‐life SE, relative to low mid‐life SE, were less likely to develop dementia (Table 2). Although the interaction between mid‐life SE and elevated SUVR was not significant, stratified models suggested a stronger association between amyloid burden and dementia in participants with high mid‐life SE (Table 3).

Conclusion

Greater mid‐life SE was associated with lower odds of developing dementia, independent of elevated SUVR. Although protective, there was no strong evidence for effect modification of mid‐life SE on the association between amyloid and dementia risk. Future longitudinal studies evaluating the potential influence of social factors measured throughout the life course are needed to inform our understanding as to what factors may preserve cognition in the presence of elevated brain pathology.
Stress system dysfunction and changes in brain volume and functional connectivity in older adults with subclinical depressive symptoms
Authors: Touron Edelweiss , de Flores Robin , Coulbaut Laurent , Palix Cassandre , Chocat Anne , Kuhn Elizabeth , Landeau Brigitte , Mézenge Florence , Roquet Daniel , Chauveau Léa , Haudry Sacha , Vivien Denis , la Sayette Vincent De , Marchant Natalie L , Chetelat Gael , Poisnel Géraldine
Published: December 2023

Background

Subclinical depressive symptoms are associated with increased risk of Alzheimer’s disease (AD). This link could be related to stress system dysfunction, known to occur in both depression and AD, and to depend notably on the hippocampus which is particularly sensitive to AD. We aimed at investigating the links between levels of blood stress markers and changes in brain regions involved in the stress response in older adults with subclinical depressive symptoms.

Method

Cognitively unimpaired older adults with (DepS; n = 73) or without (NoDepS; n = 58) subclinical depressive symptoms (defined using the 15‐item version of the Geriatric Depression Scale), from the baseline data of the Age‐Well trial (NCT02977819) were included. For each participant, levels of cortisol, epinephrine and norepinephrine were obtained from blood sampling. Moreover, the functional connectivity (FC) between, and the gray matter (GM) volume of, the hypothalamus, hippocampus and hippocampal subfields were extracted from resting‐state functional, and structural T1‐weighted, MRI. Levels of blood stress markers and neuroimaging measures were compared between groups. Regression analyses were then conducted between levels of blood markers and brain measures. Analyses were corrected for age, sex, education and anxiety symptoms with statistical significance set to p<0.05.

Result

Higher blood epinephrine level (p<0.024), and FC between the hypothalamus and the CA1 hippocampal subfield (p<0.040), was found in DepS compared to NoDepS (Fig.1). This higher epinephrine level was associated with greater FC between the hypothalamus and the CA1 (p<0.007) and Subiculum (p<0.013) subfields (Fig.2). Lower GM volume in the CA1 (p<0.008) and DG/CA2‐3‐4 (p<0.013) subfields was also found in the DepS group (Fig.3), but was not associated with epinephrine level. No significant between‐group difference in blood cortisol and norepinephrine levels was observed.

Conclusion

Subclinical depressive symptoms in aging are associated with higher blood epinephrine level related to greater FC between the hypothalamus and hippocampal subfields (CA1 and Subiculum) – suggesting an increased sympathetic nervous system activity. They are also associated with GM atrophy in specific hippocampal subfields, including the CA1 that is sensitive to AD. These two distinct mechanisms at this preclinical stage of depression may at least partly explain that depression is a risk factor for AD.
Regional cortical hypoperfusion observed in elderly adults prior to development of mild cognitive impairment
Authors: Zhang Linda , Frank Darya , Alfayate Eva , del Ser Teodoro , Medina Miguel , Strange Bryan A
Published: December 2023

Background

Cardiovascular disease is associated with increased risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD), although the underlying mechanisms are not well understood. While it has been theorised that cerebral hypoperfusion caused by heart failure may directly lead to the formation of amyloid plaques and neurofibrillary tangles characteristic of AD, it has also been suggested that decreased perfusion occurs later in disease progression. We used arterial spin labelling (ASL) MRI to compare cerebral blood flow (CBF) between cognitively unimpaired elderly individuals who would remain cognitively stable and those who would later develop MCI to determine if hypoperfusion is detectable at a preclinical stage.

Method

647 cognitively normal elderly participants with ASL and structural T1‐weighted MRI were selected from the Vallecas Project cohort, a single‐centre longitudinal study currently in its 12th year of annual follow‐up. 586 participants remained cognitively stable (CS) while 61 participants developed MCI over the course of the study. Cortical CBF maps derived from ASL images at the visit before MCI diagnosis were analysed in a voxelwise comparison with CS individuals, with age, sex, and total intracranial volume as covariates.

Result

CBF was significantly lower in the right insular cortex in future MCI converters than CS individuals (p<0.05, family‐wise error (FWE) corrected). Hypoperfusion was also significant in the anterior corpus callosum in future converters.

Conclusion

Cerebral hypoperfusion, as measured by ASL, can already be observed in individuals before the onset of clinical symptoms.
Feasibility of comprehensive heart‐brain MRI for investigating hemodynamic coupling in aging
Authors: Jarvis Kelly , Martersteck Adam , Richter Adam , Moore Jackson E. , Sridhar Jaiashre , Aristova Maria , Jin Ning , Schnell Susanne , Russell Eric , Markl Michael , Ragin Ann , Rogalski Emily J
Published: December 2023

Background

Cardiovascular risk factors have been linked with dementia risk in aging adults. However, mechanisms underlying heart‐brain hemodynamic coupling and effects on the brain remain unclear. 4D flow MRI is uniquely poised to systematically evaluate complex hemodynamics along the heart‐brain pathway. Owing to advancements yielding shorter scan times, 4D flow MRI can be acquired in approximately 7 minutes (heart) and 10 minutes (brain). This supports practical add‐on of 4D flow MRI to neuroimaging scans for comprehensive heart‐brain MRI evaluation in under an hour. We aimed to build a heart‐brain MRI acquisition and analysis framework to study relationships between hemodynamics and brain structure with age.

Method

17 healthy participants (age = 53.5±16.3[24‐76] years) underwent heart‐brain MRI at 3T (MAGNETOM Prisma, Siemens, Erlangen, Germany), including a free‐breathing whole‐chest 4D flow MRI research sequence, intracranial dual‐venc 4D flow MRI research sequence, and T1‐ and T2‐weighted structural neuroimaging. Participants were cognitively healthy and screened for history of cardiovascular and cerebrovascular problems that may influence blood flow. 4D flow MRI was used to evaluate blood flow velocities in the aorta and Circle of Willis (Figure 1: left). Mean velocity was determined on a voxel‐wise basis over the entire cardiac cycle. Volumetric and cortical thickness analysis was performed with FreeSurfer (v7.3; Figure 1: right). Left and right hippocampal and amygdala volumes were averaged and corrected for intracranial head size. We examined relationships between hemodynamics, volume and thickness measures, and age using Pearson correlations and multiple regression.

Result

Mean aortic velocity was associated with age (r = ‐0.59, p = 0.012), hippocampal volume (r = 0.68, p = 0.003), amygdala volume (r = 0.59, p = 0.012), and inferior temporal thickness (r = 0.49, p = 0.044). Figure 2. Mean velocity in the Circle of Willis (r = ‐0.49, p = 0.048), amygdala volume (r = ‐0.66, p = 0.004) and inferior temporal thickness (r = ‐0.60, p = 0.010) were also associated with age. Using multiple regression, mean aortic velocity was associated with hippocampal volume (p = 0.018) adjusting for age.

Conclusion

This study demonstrates capture of comprehensive heart and brain data in a single imaging exam for assessment of age‐related relationships in hemodynamics and brain structure. Heart‐brain MRI is a promising tool for evaluation of hemodynamic coupling along the entire heart‐brain pathway. Grant support: NIH NIA P30AG059988, P30AG072977, K01AG080070; NINDS R21NS122511:
Non‐AD pathologies, as measured using a mismatch index between regional brain metabolism and tau PET signal, are associated with age, sex, and amyloid burden
Authors: Malotaux Vincent , Colmant Lise , Dricot Laurence , Quenon Lisa , Huyghe Lara , Gérard Thomas , Ivanoiu Adrian , Lhommel Renaud , Hanseeuw Bernard J
Published: December 2023

Background

Brain hypometabolism in the absence of tauopathy may indicate the presence of non‐AD pathologies. We aimed to investigate the mismatch between regional tau pathology and brain metabolism to characterize the profile of patients suspected to have co‐pathologies.

Method

Sixty‐one clinically impaired patients, attending the Memory Clinic, performed both a [18F]‐Fluorodeoxyglucose‐PET to assess brain metabolism and a [18F]‐MK6240 Tau‐PET to estimate tau burden. To compare these images, we normalized them using data from clinically normal older adults (n = 30), resulting in FDG and tau z‐scores for 74 FreeSurfer‐defined regions. We computed intra‐subject correlation coefficients between tau and FDG data as a mismatch index between tau and metabolism. We then compared FDG and tau z‐scores using intra‐individual paired sampled t‐tests and identified patients with hypometabolism exceeding tau pathology (suspecting co‐pathologies). To increase sensitivity, the same analysis was repeated using temporal regions only. We finally evaluated demographics, cognition, and amyloid burden in the group of patients with suspected co‐pathologies.

Result

In the entire cohort, the intra‐subject FDG‐Tau correlation was significantly negative in the temporal lobe (r = ‐0.27, p<0.05), but not in the entire neocortex (r = ‐0.11), demonstrating closer association between modalities in the temporal lobe, and greater mismatch in the other regions. Twenty‐five (41%) patients had significantly greater FDG z‐scores than tau z‐scores, including thirteen (21%) with greater hypometabolism than tau pathology in the temporal lobe. These patients were older and more frequently male than patients with greater tau pathology; those with a temporal mismatch also had lower amyloid pathology (Table 1). Older ages and better cognition were associated with the mismatch index in the entire neocortex (r = 0.25/0.49, p<0.05); in addition, lower amyloid burden was associated with the temporal mismatch index (r = 0.27, p<0.05, Fig.1).

Conclusion

Patients with greater temporal hypometabolism than tau deposition are older, more frequently males, and have lower amyloid burden than patients with greater temporal tau deposition. These patients are suspected to have temporal non‐AD pathologies.
CSF Aβ42/40 is associated with neurodegeneration independently of CSF p‐tau in the earliest AD continuum
Authors: Cacciaglia Raffaele , Falcon Carles , Shekari Mahnaz , Salvadó Gemma , Milà‐Alomà Marta , Huguet Jordi , Garcia Marina , Kollmorgen Gwendlyn , Carboni Margherita , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo
Published: December 2023

Background

Soluble Aß dyshomeostasis is thought to be the earliest detectable alteration in AD, but is believed to have little impact on neurodegeneration. Conversely, the onset of tau pathology in the presence of Aß drives subsequent neurodegeneration. Here, we aimed to assess the independent contribution of soluble Aß and tau dyshomeostasis to neurodegeneration, in the earliest stages of the AD continuum.

Method

The first 330 consecutive participants of the ALFA+ study with available longitudinal (3.45±0.24 y) MRI, CSF Aß42, Aß40, p‐tau181, and NfL at baseline were included. CSF biomarkers were assessed with the Roche NeuroToolKit robust prototype immunoassays and p‐tau181 with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (Roche Diagnostics International Ltd). Gray matter volume (GMv) changes were computed voxelwise using SPM12 on T1w scans. Hippocampal subfields were segmented using ASHS on high‐resolution acquisitions. To detect regions showing early neurodegeneration, correlations between CSF NfL and GMv changes were sought. Then, GMv and hippocampal subfields changes were sought in association with CSF Aß42/40 and CSF p‐tau181, both alone and after controlling for the other biomarkers. The interactive effect of CSF p‐tau181 and Aß status (CSF Aß42/40 < 0.071) on brain structure was determined.

Result

Table 1 shows sample’s characteristics. CSF NfL concentrations were associated with longitudinal GMv atrophy in the medial and inferior temporal areas (Fig. 1A). CSF Aß42/40 significantly predicted GMv atrophy in the hippocampus bilaterally, alone and when controlling for CSF p‐tau181 and NfL (Fig. 1B‐C). CSF p‐tau181 interacted with Aß status to predict GMv atrophy in the posterior hippocampus bilaterally (Fig. 1D). Longitudinal GMv atrophy in the hippocampal subfields were confirmed in association with CSF Aß42/40 in the bilateral CA1, dentate gyrus and BA35 (Table 2).

Conclusion

Independently of p‐tau, early Aß dyshomeostasis is associated with longitudinal GMv atrophy in AD‐sensitive brain areas in the early AD continuum. As expected, tau levels were associated with additional atrophy in these regions in Aß+ individuals. Pathophysiological alterations other than Aß, but correlated with CSF Aß levels, might contribute to the observed atrophy patterns. Control of the earliest pathophysiological alterations in AD may have a relevant impact on neurodegeneration, even at the earliest preclinical stages.
Vascular contribution to the preclinical Alzheimer’s disease pathological changes: Insights from the EPAD cohort
Authors: Lorenzini Luigi , Maranzano Alessio , Tranfa Mario , Collij Lyduine E. , Sudre Carole H , Wolz Robin , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Payoux Pierre , Martinez‐Lage Pablo , Ewers Michael , Chetelat Gael , Waldman Adam , Wardlaw Joanna M , Fox Nick C , Ritchie Craig W , Scheltens Philip , Visser Pieter Jelle , Wink Alle Meije , Mutsaerts Henk‐Jan , Gispert Juan Domingo , Ingala Silvia , Barkhof Frederik
Published: December 2023

Background

The role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.

Method

We included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aß1‐42; CSVD indices (visual assessment for perivascular spaces [PVS] in the basal ganglia [BG] and centrum‐semiovale [CS], periventricular and deep white matter hyperintensities [WMHs], presence of lobar or deep cerebral microbleeds [CMBs], and lacunes, and quantification of global and lobar WMH volumes) and Aß1‐42 and p‐Tau181, including an interaction between CSVD indices and Aß1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.

Result

Higher FRS scores were associated with lower CSF Aß1‐42 (ß = ‐0.18; p<0.001) and higher P‐tau181 (ß = 0.21; p<0.001). Aß1‐42 was negatively associated with all CSVD markers (all p<0.001; Figure‐2). We found stronger association between Aß1‐42 and P‐tau181 in participants with higher Fazekas deep and periventricular (p‐interaction<0.005) scores, and higher regional WMH (all p‐interactions<0.005) volumes. Using SEM, the CSVD‐burden latent factor fully mediated the association between FRS and Aß1‐42 (indirect effect: ß = ‐0.03; p<0.001). Aß1‐42 did not significantly predict the CSVD‐burden latent factor. We observed a significant direct effect of Aß1‐42 on P‐tau181 levels (ß = ‐0.14; p<0.001) and HCV (ß = 0.06; p<0.05), and of P‐tau181 levels onto HCV (ß = ‐0.05; p<0.05). A significant indirect, but not direct, effect of the latent factor on both P‐tau181 (indirect effect: ß = 0.36; p < 0.05) and HCV (indirect effect: ß = ‐0.24; p < 0.05) through Aß1‐42 was observed.

Conclusion

Expression of cerebrovascular pathology fully mediates the effects of vascular risk factors on amyloid and accelerates manifestation of downstream biomarkers in the preclinical phases of AD, stressing the importance of vascular‐protective treatments.