Most recent paper

Alzheimers Dement. 2024 Dec;20 Suppl 2:e085561. doi: 10.1002/alz.085561.

ABSTRACT

BACKGROUND: In the last decade, extensive research has emerged into understanding the impact of risk factors for Alzheimer's Disease (AD) on brain function in pre-symptomatic stages. Here, we focused on the apolipoprotein e4 (APOEe4) gene, the major genetic risk factor for sporadic AD, and its effect on brain function in early adulthood.

METHOD: In the first part of the study, we systematically reviewed the multimodal functional neuroimaging literature, exploring its relationship with cognition, and the potential effects of other variables including the demographics, other risk factors, and methodological and analytical choices. While the studies demonstrated consistent alterations of APOEe4 carriers in brain connectivity and activity; the results of fMRI studies covered mostly the differences in the directionality using standard connectivity and activity measures. In the second part of this study, we aimed to address this gap by using the graph theory analysis to explore the dynamic behaviour of the six resting-state networks of interest in young APOEe4 carriers versus non-carriers (n=129, aged 17-22).

RESULT: Average Path Length and Closeness Centrality were consistently disrupted, pointing to network reorganisation in multiple resting-state networks, albeit using different mechanisms.

CONCLUSION: This study is the first to demonstrate the restructuring of multiple resting-state networks in young adults modulated by the APOE genotype.

PMID:39785711 | DOI:10.1002/alz.085561

Alzheimers Dement. 2024 Dec;20 Suppl 2:e084078. doi: 10.1002/alz.084078.

ABSTRACT

BACKGROUND: The aim of this study was to explore the correlation between brain functional alterations and cerebrospinal fluid (CSF) pathological biomarkers in Alzheimer's disease (AD) patients.

METHOD: A total of 39 individuals were recruited, including 23 AD patients and 16 control subjects. All subjects underwent a battery of neuropsychological examinations, CSF measurement and multimodal magnetic resonance imaging scans. Independent component analysis was used to investigate the variations of functional connectivity (FC) between the two groups by utilizing the resting-sate functional MRI (RS-fMRI) data. Differences in ALFF and ReHo between the two groups were also calculated. Then correlation analyses were used to estimate the possible association between functional alterations and CSF β-amyloid (Aβ1-42.) and tau.

RESULT: Multiple inter- and intra-network functional connections were altered in AD patients compared to the Non ADCI group. In the AD group, ALFF decreased in the right Superior Frontal Gyrus, Middle Frontal Gyrus, left superior temporal gyrus. and increased in the right cerebellum anterior lobe, and caudate nucleus as compared to Non-AD CI group (p < 0.001). In addition, ReHo decreased in the right insula and left middle temporal gyrus (p < 0.001). Dynamic fluctuations of CSF Tau were observed to be associated with changes in FC between VN and PCC, FC of SMN, as well as the altered ReHo in the right insula and left middle temporal gyrus. Compared the AD group with the non-AD CI group, the aforementioned altered functional brain connectivity, with the exception of FC in the PCC and VN, was significantly associated with a decrease in CSF Aβ1-42.

CONCLUSION: AD patients have exhibited functional changes in more than one brain region. These changes are linked to the variations of Tau protein and Aβ1-42 in CSF, with Aβ1-42 having a particularly large impact on brain network function. From an imaging standpoint, this study validated the impact of pathological changes on brain function in AD.

PMID:39785698 | DOI:10.1002/alz.084078

Alzheimers Dement. 2024 Dec;20 Suppl 2:e089176. doi: 10.1002/alz.089176.

ABSTRACT

BACKGROUND: Cognitive Reserve (CR) refers to the brain's ability to maintain optimal cognitive function despite damage or pathology. The neural implementation of CR is a major research focus, and resting-state functional connectivity (RSFC) has emerged as a promising imaging correlate of CR. We assessed RSFC as a function of two different proxy measures of CR and further assessed the impact of these brain networks on longitudinal cognitive performance in a sample of cognitively unimpaired (CU) individuals at risk of Alzheimer's disease (AD).

METHOD: Analyses were conducted in 328 CU individuals from the ALFA cohort (mean age=60.8, SD=4.74) with available CSF Aβ, p-tau, resting-state fMRI and longitudinal cognitive assessment (average follow-up time=3.35 years, SD=0.53). CSF Aβ42 and Aβ40 were assessed with the exploratory NeuroToolKit, while p-tau181 was measured with the Elecsys® Phospho-Tau (181P) CSF immunoassay (both Roche Diagnostics International Ltd). We examined the impact of years of education (YOE) and global score of the Cognitive Reserve Questionnaire (CRQ) on the RSFC amongst 246 brain regions of the Brainnetome atlas using the CONN toolbox, selecting a cluster threshold of p<0.005, and adjusting or the effects of age, sex, and APOE status.

RESULT: Of the entire sample, 38.4% had positive CSF Aβ42/40 markers. YOE was related to an increased RSFC between regions of the salience network and the anterior default-mode network (DMN). Increased negative RSFC was found as a function of YOE between primary visual areas and regions of the executive control as well as dorsal attention (Figure 1). In models adjusted by CSF biomarkers, the increased RSFC between the anterior DMN and salience regions predicted better PACC score over time and further modulated the association between CSF Aβ42/40 and longitudinal PACC (Figure 2). CRQ score was associated with a decreased RSFC between the posterior DMN and inferior temporal areas. These patterns of reduced RSFC significantly mediated the impact of CSF Aβ42/40 on longitudinal memory performance (Figure 3).

CONCLUSION: RSFC may provide insights into the mechanisms relating CR and cognitive resilience in preclinical AD. Further, the expression of RSFC patterns may serve as an outcome in intervention studies aiming to boost CR.

PMID:39785623 | DOI:10.1002/alz.089176

Alzheimers Dement. 2024 Dec;20 Suppl 2:e088685. doi: 10.1002/alz.088685.

ABSTRACT

BACKGROUND: The neural basis of memory aging remains elusive. The default mode network (DMN) supports memory encoding and retrieval, and its connectivity decreases in aging. Young adults with larger differences in resting-state functional connectivity (rsFC) between higher-order DMN and lower-order sensory/motor network (SMN) have better cognition and memory. We combined resting-state and task-based fMRI during an associative memory task to explore how this cross-hierarchical contrast of rsFC is linked to memory aging.

METHOD: We included resting-state prior to (an object-scene-pair encoding) task fMRI from 16 young adults (YA; 24.6 ± 3.6 years; 7 females) and 42 cognitively normal older adults (OA; 76.8 ± 6.9 years; 24 females) in the Berkeley Aging Cohort Study. We subtracted the averaged rsFC within lower-order regions from higher-order ones, and correlated the cross-hierarchy contrast of rsFC with age and memory task performance. Brain function contrast between the higher and lower order regions may also manifest as the temporal difference/delay of cortical activation, seen in propagating waves between hierarchical cortices. The propagating number (i.e., frequency) in each direction ("High-to-low" or "Low-to-high") was therefore also correlated with memory performance and activation in anterior-temporal (AT), posterior-medial (PM), and hippocampal (HPC) memory regions during task-fMRI.

RESULT: Among OAs, cross-hierarchy contrast of rsFC decreased with aging (Spearman's ρ = - 0.32, p = 0.040) and in females (p = 2.3 ×10-3). OAs with lower rsFC contrast had worse memory during retrieval (ρ = 0.36, p = 0.019; Figure 1). Memory scores were not correlated with mean rsFC within higher-order regions or lower-order ones. Propagating number along the "Low-to-high" direction decreased in OAs. More propagation was associated with better memory and lower task-evoked activation in AT, PM, and HPC regions (all ρ strength > 0.35, p < 0.030; Figure 2&3).

CONCLUSION: Patterns of resting-state functional connectivity related to hierarchical cortical organization are associated with aging and memory decline. In particular, slow propagating waves of cortical activation transiting across these hierarchies may serve a preparatory function, readying the brain for memory formation, a process that is affected by aging.

PMID:39785538 | DOI:10.1002/alz.088685

Alzheimers Dement. 2024 Dec;20 Suppl 2:e087143. doi: 10.1002/alz.087143.

ABSTRACT

BACKGROUND: Non-linear statistical analyses on resting-state fMRI (rs-fMRI) using complexity measures have demonstrated progressive decline in complexity from cognitively normal subjects (CN) to patients with Mild Cognitive Impairment (MCI) and patients with Alzheimer's disease (AD). While complexity has been shown to be negatively associated with tau-PET, the association with amyloid or effects of genetic characteristics (APOE4) remains unknown.

METHOD: From the Alzheimer's Disease Neuroimaging Initiative (ADNI3) we identified participants with tabulated SUVR values for amyloid and tau as well as one resting state fMRI scan for the same visit. The rs-fMRI complexity was calculated as Multiscale Sample Entropy (MSE) (r=0.5, m=2, scale=6). SUVR values from precuneus, parahippocampal, inferior temporal and entorhinal regions were used in a multivariate generalized linear model to investigate the adjusted independent effects to corresponding rs-fMRI complexity. Whether such effects were modified by either diagnosis (CN, MCI, AD) or APOE4 status (# alleles) were tested using the interaction terms in the multivariate model. Age and gender were controlled for all models.

RESULT: The final cohort consisted of 127 subjects (Table 1). We observed statistically significant negative associations between complexity and tau in parahippocampus, inferior temporal gyrus and precuneus (Table 2A). Diagnostic status does not modify these associations, however, APOE4 status showed a statistically significant interaction effect for tau and complexity in precuneus (Table 2C). For amyloid no associations nor interaction effects were found (Table 2B).

CONCLUSION: Our study confirmed previously reported statistically significant inverse relationship between rs-fMRI complexity and tau-PET, which is indicative of disfunction of neuronal signaling in the presence of tauopathy. While diagnostic classification showed no effects, the APOE4 genetic risk had a strong modifying effect leading to a stronger negative relationship between tau-PET and fMRI-complexity. The null-finding for amyloid was expected, since, while the presence of amyloid increases risk for cognitive decline, it is the occurrence of tau that leads to cognitive decline and neurodegeneration. Overall, genetic risk potentially increases the prevalence of amyloid in this cohort and consequentially leads to a cumulative and more pronounced decrease in rs-fMRI complexity in the presence of tau.

PMID:39785514 | DOI:10.1002/alz.087143

Alzheimers Dement. 2024 Dec;20 Suppl 2:e092088. doi: 10.1002/alz.092088.

ABSTRACT

BACKGROUND: The extent of neurofibrillary changes, one of the pathological hallmarks of AD, correlates with the severity of AD in dementia. The brainstem is known to be the site of neurofibrillary changes in the early stages of Alzhimer's disease. The neurotransmitter system in the brainstem processes information from subcortical and cortical circuits affect to various cognitive and behavioral responses in the cerebral cortex. This study aims to investigate we cluster the brainstem with respect to how they connect to the cortex and focus on the brainstem cluster of differences according to the subtypes of AD.

METHOD: We acquired the resting state fMRI data from 137 patients with several dementia types (96 females, mean age = 70.31 ± 7.13), which were collected from the BICWALZS (Biobank Innovation for chronic Cerebrovascular disease With ALZheimer's disease Study). They were divided into four dementia subtype groups: subjective cognitive decline(SCD) mild cognitive impairment(MCI)-β-amyloid negative(MCI-), MCI-β-amyloid positive (MCI+), and AD (N=33). For physiological denoising in functional neuroimaging data of the brainstem, we used FSL's ICA-AROMA, a data-driven denoising approach. We extracted each regional-mean time series using Schaefer 200 atlas and voxel-wise time series of brainstem. A functional connectivity matrix is composed of the brainstem-to-cortex that regressed out dominant pattern, which is the weights of the connectivity across all 200 cortical regions that the brainstem had. Then we clustered the brainstem based on modularity according to the extent of connectivity similarity between the brainstem and cortex via connectivity matrix profiles. Finally, our study focused that comparison the pattern of clustering according to the subtypes of AD.

RESULTS: We found that each community in the brainstem is a group with a similar pattern of functional connectivity to the cortex. Different brainstem communities are observed in the distinct in accordance with the subtypes of AD, suggesting that in each disease group can characterize specific brainstem communities with functional connectivity to the cerebral cortex.

CONCLUSION: Different patterns of clusters in different subgroups of dementia may explain functional abnormalities in the brainstem as dementia progresses. The future study will characterize each connection between clusters of brainstem and cortical regions.

PMID:39785459 | DOI:10.1002/alz.092088

Alzheimers Dement. 2024 Dec;20 Suppl 2:e090994. doi: 10.1002/alz.090994.

ABSTRACT

BACKGROUND: The common marmoset (Callithrix jacchus) is an important animal model in neuroscience and neurological diseases, presenting primate-specific evolutionary features such as an expanded frontal cortex. We established a new consortium with funding support from the National Institute on Aging to generate, characterize, and validate MArmosets as Research MOdels of AD (MARMO-AD). This consortium develops and studies gene-edited marmoset models carrying genetic risk for AD, comparing them against wild-type aging marmosets from birth throughout their lifespan, using non-invasive longitudinal assessments. Here, we aim to characterize healthy aging trajectories by investigating their resting state functional connectivity in a population of marmosets.

METHOD: We imaged a cohort of 25 marmosets (17 males, 8 females) across the lifespan (8 to 150 months) using a dedicated 9.4T/30cm Bruker MRI scanner. The animals were acclimated to restrainers and head-fixation helmets and imaged awake. EPI images (500 µm isotropic) were acquired for 1 hour and 20 minutes, yielding 2400 whole-brain volumes. The images were pre-processed for fMRI using AFNI and FSL. For each run, the first ten time points were removed for magnetization to reach a steady state. The images were despiked, and spatially aligned. Slice timing was corrected, and phase-encoding distortion was corrected using FSL. Subsequently, brain images were registered to the Marmoset Brain Mapping V3 template, and brain-wide connectomics were calculated using the GRETNA toolbox.

RESULT: Our group has shown through structural investigations (voxel-based morphometry and white matter tractography) that several cortical clusters are affected by aging (Figure 1, Top Left). Here, with resting state fMRI, we show that many brain regions that change size with aging also show accompanying changes in their functional connectivity strength (Figure 1, Right). Integrating resting-state fMRI with structural investigations will allow us to understand how these affected structures work together in a dynamic network.

CONCLUSION: Our work is the first to thoroughly describe the changes in resting state functional connectivity in the marmoset brain during normal aging, a valuable model for AD. This research will establish normative baselines for changes in marmoset brain connectivity with aging to evaluate our genetically engineered marmoset models of AD.

PMID:39785372 | DOI:10.1002/alz.090994

Alzheimers Dement. 2024 Dec;20 Suppl 2:e093207. doi: 10.1002/alz.093207.

ABSTRACT

BACKGROUND: Traditional functional connectivity is calculated as the correlation between resting-state fMRI time series from pairs of brain regions or networks. Our innovative method extracts time series information from cross-correlations curves between brain regions, thus deriving the relative duration of functional connections. These temporal analysis methods provide a means for examining how the timing of brain connections is affected across the dementia spectrum. This study extends previous research efforts into understanding the neural correlates of dementia by applying innovative resting-state functional connectivity analysis methods to a sample of cognitively intact older adults (HC), individuals with mild cognitive impairment (MCI), and Alzheimer's disease (AD).

METHOD: 109 participants were included in this analysis (HC: n=47, 29 female, age=72.13±4.68; MCI: n=32, 18 female, age=73.84±5.14; AD: n=30, 19 female, age=77.37±6.45). All study participants were administered the Mini Mental Status Examination (MMSE), and completed MP2RAGE structural imaging and two 15-minute resting fMRI scans. Cross-correlation curves were constructed utilizing the Pearson correlation coefficient between pairs of times series for each of the 17 brain networks in the Yeo et al. parcellation. Correlation values were recorded at each of ±20 lags by shifting one of the time points by one volume. Sustained connectivity is derived from the full width at half maximum of the curve (Figure 1A) whereas lag-based connectivity utilizes the correlation value at each lag. T statistics and p-values are reported for across-group connectivity values. Partial correlations were computed between connectivity measures and MMSE scores. All results include controlling for the effects of mean head motion, age, and sex.

RESULT: Sustained connectivity demonstrated distributed increases across groups (Figure 1B; HC<MCI<AD; pFDR<.05). At zero-lag, we see decreased connectivity in MCI and AD compared to HC; however, as lag-based connectivity is increased, we see increases in connectivity corresponding to diagnostic groups (Figure 2; HC<MCI<AD). Across study participants, both sustained and lag-based connectivity were negatively correlated with MMSE scores (Figure 3; pFDR <.05).

CONCLUSION: Taken together, these findings suggest that functional connections between brain networks persist longer across disease states and that this longer duration of connectivity may reflect increased cognitive demand related to underlying cognitive processes.

PMID:39785323 | DOI:10.1002/alz.093207

Alzheimers Dement. 2024 Dec;20 Suppl 2:e095826. doi: 10.1002/alz.095826.

ABSTRACT

BACKGROUND: To understand the progression of Alzheimer's disease (AD), neuroimaging and biomarker research relies increasingly on sophisticated data analysis techniques that are often restricted to expert lab environments. Here, we demonstrate how complex analyses on modeling tau spreading across interconnected brain regions from our previous studies (e.g., Franzmeier et al., Nat Commun, 2020; 2024, Sci Adv, 2020) can be replicated using the cloud-based Alzheimer's Disease Workbench (ADWB) environment. We illustrate how data analyses can transition from restricted lab environments to open cloud-based workspaces, highlighting the potential for data sharing, transparency and collaborative analysis in AD research via cloud-based solutions.

METHODS: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were re-analyzed in the ADWB environment. The analyses involved combining resting-state fMRI with longitudinal tau-PET imaging data to investigate the relationship between brain connectivity and tau accumulation. We illustrate the role of the ADWB as an integrated workspace where datasets can be uploaded, explored, and analyzed using a suite of tools, including Python and R. Within this environment we illustrate how sophisticated data analyses can be replicated in shared environments to facilitate collaborative research efforts.

RESULTS: Replicating key findings from our original studies, we demonstrate that interconnected brain regions show correlated tau accumulation, and that tau spreads from local epicenters across connected brain regions, indicating potential trans-neuronal tau propagation. We provide shared data and code for running and visualizing analyses on connectivity-mediated tau spreading, enhancing the accessibility and reproducibility of neuroimaging analyses in AD.

CONCLUSION: The AD Workbench environment effectively supports complex neuroimaging analyses, facilitating data sharing and collaborative research using open-access datasets such as ADNI. By enabling researchers to replicate and extend existing studies, ADWB can enhance our understanding of AD mechanisms and foster collaborations across different research sites and groups. We underscore the role of cloud-based and open-access solutions in neuroimaging research that can make advanced data analysis techniques available to a broader research community.

PMID:39785309 | DOI:10.1002/alz.095826

Alzheimers Dement. 2024 Dec;20 Suppl 2:e092733. doi: 10.1002/alz.092733.

ABSTRACT

BACKGROUND: The ε4 allele of the apolipoprotein E (APOE4+) genotype and aging synergistically contribute to the risk of Alzheimer's disease (AD), but the mechanisms underlying their influence are not completely understood. The methylation of ELOVL2 DNA accounts for 70% of the variance in the aging epigenetic clock. The ELOVL2 gene is essential for synthesizing long polyunsaturated fatty acids, crucial for cell membrane integrity, inflammation modulation, and energy maintenance. This study investigated the impact of APOE genotype and ELOVL2 methylation on EEG alpha rhythm and functional MRI (fMRI) resting-state functional connectivity (rsFC) of brain networks in non-demented adults during aging.

METHOD: We examined EEG alpha sub-bands power and individual alpha peak frequency (IAPF) and the fMRI rsFC in 151 non-demented volunteers, age range 20-84 years, stratified by APOE genotype. APOE ε3/ε3 subgroup (APOE4-) included 104 subjects, APOE ε4/ε3 (APOE4+) subgroup - 47 subjects. ELOVL2 cg16867657 methylation was examined in the blood in subgroup of 56 individuals (35 APOE4- and 21 APOE4+). The individuals underwent fMRI tsFC of the brain using the CONN Matlab/SPM-based toolbox (Whitfield-Gabrieli and Nieto-Castanon, 2012). Informed written consent was obtained from all participants. All subjects underwent a neurological examination and cognitive screening.

RESULT: The presence of the APOE4+ genotype was associated with more pronounced alpha rhythm slowing and more pronounced decrease of fMRI rsFC during aging. Age-related increase of ELOVL2 methylation was observed. The partial correlation analysis, with age as a covariate, revealed a significant correlation between ELOVL2 methylation and IAPF.

CONCLUSION: More pronounced alpha rhythm slowing and fMRI rsFC reduction in APOE4+ carriers during aging can be linked to synaptic dysfunction and deterioration of white matter integrity. Impaired lipid metabolism, driven by age-dependent ELOVL2 methylation, may accelerate the impact of the APOE4+ genotype on neurophysiological alterations during aging. These changes increase the risk of AD developed.

FUNDING: This study was supported by Russian Science Foundation (Project No. 19-75-30039 to TA genotyping; Project No. 22-15-00448 to NP, RK, VF, EK EEG and fMRI analysis and MP for genotyping) and by Ministry of Science and Higher Education of the Russian Federation (Agreement 075-10-2021-093 project GEN-RND-2017).

PMID:39785263 | DOI:10.1002/alz.092733

Alzheimers Dement. 2024 Dec;20 Suppl 7:e087231. doi: 10.1002/alz.087231.

ABSTRACT

BACKGROUND: Cognitive reserve (CR) and Brain Maintenance (BR) are constructs defined at a theoretical level (Stern et al., Neurobiol Aging, 2021 Apr, 124:100-103). Our aim was to propose a reproducible procedure to compare CR-like of BR-like mechanisms underlying interindividual differences in memory stability.

METHOD: Leveraging data from the Lifebrain consortia (Walhovd et al. Eur Psychiatry. 2018 Jan;47:76-87) we gathered information regarding 1) episodic memory (EM) stability, defined as those subjects showing no negative memory changes across two time point assessments (i.e., change ≥0), 2) brain structure and 3) brain functionality (resting-state functional magnetic resonance imaging [MRI]) changes). We designed a unified approach where at each step an analysis between EM and multimodal MRI-based measures provides a general metric, referring to either associations between EM and hippocampal (HC) volume changes, or to EM and fMRI connectivity changes (see Figure). This aimed to distinguish a 'BM - Pathway 1' identifying those subjects presenting a correspondence between both stability of EM and of HC volumes (i.e x≥0 & y≥0 quadrants of the upper left scatterplot) and a, 'BM - pathway 2' reflecting a correspondence between stability of EM and HPC fMRI functionality (i.e x≥0 & y≥0 quadrants of the bottom right scatterplot). Finally, a CR - pathway ('deviant cases' in Figure) was defined for subjects where a discrepancy between EM stability and their neural substrates was found (i.e. x>0 and y<0 quadrants in both scatterplots).

RESULT: Findings obtained from N = 532 participants (67.8 years at baseline, 294 women) revealed that N = 275 exhibited memory stability over time. Present analyses show that from those, N = 166 (60%) could be classified as BM -pathway 1 at the first step, whereas N = 109 (40%) cases were classified as CR - pathway. Further results from a subsample, indicate that CR - pathway cases exhibited a positive change in EM and negative in HC volumes, evidencing reductions in functional connectivity between HC and the Medial Prefrontal node from the dorsal Default Mode Network.

CONCLUSION: The present approach combining structural and functional MRI to study CR and BM constructs shall provide new relevant empirical data helping to clarify the conceptual boundaries between these categories.

PMID:39785012 | DOI:10.1002/alz.087231

Alzheimers Dement. 2024 Dec;20 Suppl 7:e088841. doi: 10.1002/alz.088841.

ABSTRACT

BACKGROUND: Normal aging is associated with alterations of functional connectivity (FC) in brain neuronal networks. Altered network connectivity may be associated with accelerated cognitive decline. Physical activity is considered a beneficial lifestyle factor for maintaining cognitive health. Higher intensities of physical activity may induce structural and functional changes in the brain, particularly in regions involved in cognitive functions, such as memory, attention and executive functions. However, the underlying neural mechanisms are not widely investigated. Our aim was to examine the association between resting-state FC of brain networks and baseline physical activity in healthy older adults.

METHOD: We analyzed baseline resting-state fMRI and baseline physical activity data of 149 healthy older adults (mean age: 68 years) from the AgeGain study. Physical activity was measured by using actigraphs worn for 7 days. Different intensities were measured, such as light, mean and moderate-to-vigorous activity (min/d). We used Independent Component Analysis (ICA) and seed-based approaches to examine brain network activity in the Default Mode Network (DMN), Salience Network (SAL), Central Executive Network (CEN), Visual Network (VN) for cognitive effects and Sensorimotor Network (SMN) for physical effects.

RESULT: We observed statistically significant associations between functional activation within SMN and light physical activity and spatially restricted effects for DMN and moderate-to-vigorous physical activity (p <.01 uncorrected). In addition, we observed an overlap on frontal activation across DMN, SMN and SAL. Results of the seed-based analysis will be presented at the conference.

CONCLUSION: Light to higher intensities of physical activity showed an association with higher functional activation of networks previously associated with cognitive decline and physical activity. This agrees with the notion that physical activity may be a protective factor against cognitive decline. Further research is needed to test the replicability of these results.

PMID:39784770 | DOI:10.1002/alz.088841

Alzheimers Dement. 2024 Dec;20 Suppl 7:e088302. doi: 10.1002/alz.088302.

ABSTRACT

BACKGROUND: Greater physical activity and better sleep are associated with reduced risk of cognitive decline and dementia among older adults, but little is known about their associations with measures of brain function and neuropathology.

METHOD: This study investigated potential independent and interactive cross-sectional relationships between actigraphy-estimated total volume of physical activity (TVPA) and sleep patterns [i.e., total sleep time (TST), sleep efficiency (SE)] with cognitive performance (n = 157). In a subset of participants, the physical activity and sleep measures were also evaluated in relationship to resting-state functional magnetic resonance imaging (rs-fMRI) measures of large-scale network connectivity, and positron emission tomography (PET) measures of amyloid-β (n = 135). Participants were part of the BIOCARD study including 136 cognitively normal individuals and 21 participants with mild cognitive impairment (mean age = 71.7 years). Using linear regression analyses, we assessed the association between TVPA, TST, and SE with cognition, connectivity within the default-mode, salience, and fronto-parietal control networks, and with network modularity, a measure of network segregation.

RESULT: Greater TVPA and SE each were positively associated with better global cognitive composite scores and executive function. Importantly, a TVPA by SE interaction suggested that adults with the poorest SE experienced the greatest benefit from physical activity in relation to cognition. In the imaging subsample, higher TVPA and SE were independently associated with greater network modularity, although the positive relationship of SE with modularity was only present in amyloid-negative individuals. Additionally, higher TVPA was associated with greater connectivity within the default-mode network, while greater SE was related to greater connectivity within the salience network. In contrast, longer TST was associated with lower network modularity, particularly among amyloid-positive individuals, suggesting a relationship between longer sleep duration and greater network disorganization. Physical activity and sleep measures were not associated with amyloid positivity.

CONCLUSION: These data suggest that greater physical activity levels and more efficient sleep may promote better cognition and more segregated and potentially resilient functional networks, as well as greater functional connectivity within specific large-scale networks. Additionally, the relationship between sleep and functional networks connectivity may depend on amyloid status while associations with physical activity may be independent of amyloid status.

PMID:39784764 | DOI:10.1002/alz.088302

Alzheimers Dement. 2024 Dec;20 Suppl 2:e088384. doi: 10.1002/alz.088384.

ABSTRACT

BACKGROUND: Resting-state functional MRI (rs-fMRI) has been widely used for assessing disease progression in AD. It becomes, however, notoriously variable at disease's prodromal stage when the cognitive functions are fluctuating while declining at the same time during this transitional period, which reduces its sensitivity in AD detection. Olfactory deficit has been shown to be an early sign of AD when the cognition decline is indistinguishable from normal aging. In this study, we investigated our hypothesis that functional connectivity (FC) between olfactory network and default mode network (DMN) will be disrupted in early AD.

METHOD: Longitudinal rs-fMRI data of 42 clinically diagnosed MCI were collected at 1st-time point from ADNI database (Table 1). The piriform cortex was manually segmented as the seed of POC (Figure 1A). The FC between POC and DMN was evaluated and analyzed within and between MCI-AD converters and non-converters.

RESULT: Compared to MCI non-converters, AD patients' FC between POC and DMN was significantly weaker (p<0.05, Table 1 and Figures 1-2), while there was no significant difference in regards of POC-DMN FC between MCI-AD converters and non-converters at the baseline (p>0.05). When the disease was progressed to AD, the FC between right piriform cortex and precuneus/PCC was significantly reduced (p=0.04). The FC of POC to DMN in MCI non-converters was significantly correlated with cognitive score CDR-cog, but not in MCI-AD converters (Figure 2).

CONCLUSION: The FC between POC and DMN was disrupted in early AD. The observed disruption established a mechanistic link between olfactory deficits and cognition decline in AD. The functional dysconnectivity between POC and DMN could be an objective imaging marker for MCI conversion to AD.

PMID:39784390 | DOI:10.1002/alz.088384

Alzheimers Dement. 2024 Dec;20 Suppl 2:e086460. doi: 10.1002/alz.086460.

ABSTRACT

BACKGROUND: The accumulation of tau tangles and beta-amyloid (Aβ) are hallmarks of Alzheimer's disease (AD). Despite the hypothesis that Aβ may trigger tau spread across remote brain regions, the specific pathological processes remain unclear.

METHODS: Our study utilized 18F-Florbetaben Aβ positron emission tomography (PET), 18F-MK6240 tau PET, and resting-state functional magnetic resonance imaging (rs-fMRI). We included 361 healthy control (HC) subjects from the Northern Manhattan Study of Metabolism and Mind (NOMEM) [mean age 64.96 ± 3.17 years, 230 females]. Among them, 46 subjects underwent follow-up scans at 2 to 3 year intervals. Additionally, 120 HC subjects from the Brain Health Imaging Institute (BHII) studies were included (mean age 68.71 ± 6.16 years, 54 females). Cross-sectional elderly subjects were categorized into four groups based on normal (n) and abnormal (a) levels of Aβ and tau, as compared to young normative subjects (age < 40): nAβ/nTau, aAβ/nTau, nAβ/aTau, and aAβ/aTau. Assortativity, a graph theory metric, was computed on the average functional connectivity maps for each group. We also compared the connectivity between the limbic network and other functional networks among these groups of subjects. Finally, using longitudinal subjects, we explored the role of between-network connectivity of the limbic network in mediating the association between cortical Aβ in six functional networks and annual tau elevation in the limbic network.

RESULTS: Figure 1 illustrates that among the four groups in both datasets, aAβ/nTau subjects displayed the highest assortativity values (0.767 for NOMEM and 0.627 for BHII). In both datasets, aAβ/nTau showed significant increases (t-value > 4.49, p-value < 0.0001) in between-network connectivity of the limbic network (Figure 2) compared with the other three groups. 14 Aβ-positive subjects achieved highly significant results (p-value < 0.013) for indirect relationships in all six functional networks (Figure 3).

CONCLUSION: Our study highlights the early accumulation of Aβ and its role in increasing between-network connectivity. We also demonstrated that between-network connectivity mediates the remote relationships between Aβ and tau pathologies in the preclinical stages of AD.

PMID:39784375 | DOI:10.1002/alz.086460

Alzheimers Dement. 2024 Dec;20 Suppl 2:e087302. doi: 10.1002/alz.087302.

ABSTRACT

BACKGROUND: Amyloid-β (Aβ) pathology affects resting state functional connectivity (RSFC), even in cognitively unimpaired (CU) individuals. However, the impact of such an aberrant RSFC on cognitive decline is yet to be determined. Moreover, most prior research focused on fibrillary Aβ deposition to predict RSFC, while early Aβ dysmetabolism as reflected by cerebrospinal fluid (CSF) concentrations has received less attention. We assessed RSFC as a function of both CSF Aβ and p-tau in CU individuals, and further analyzed the impact of biomarker-dependent RSFC on the longitudinal cognitive performance.

METHOD: Analyses were conducted in 328 CU individuals from the ALFA cohort (mean age=60.8, SD=4.74) with available CSF Aβ, p-tau, resting-state fMRI and longitudinal cognitive assessment (average follow-up time=3.35 years, SD=0.53). CSF Aβ42 and Aβ40 were assessed with the exploratory NeuroToolKit, while p-tau181 was measured with the Elecsys® Phospho-Tau (181P) CSF immunoassay (both Roche Diagnostics International Ltd). RSFC was computed amongst 246 brain regions of the Brainnetome atlas using the CONN toolbox, selecting a cluster threshold of p<0.005. The effects of CSF biomarkers on RSFC were adjusted by age, sex, years of education and APOE-ε4 status.

RESULT: Of the entire sample, 38.4% had positive CSF Aβ42/40 markers. Low CSF Aβ42/40 ratios were associated to a higher RSFC between visual areas and anterior as well as posterior subdivisions of the default-mode network (DMN) (Figure 1). These results survived a family-wise error rate p-value<0.005. High levels of CSF p-tau were related to a higher RSFC between inferior temporal areas and the anterior DMN, as well as a reduced RSFC between visual and the somatomotor network. The Aβ-related higher RSFC significantly predicted longitudinal cognitive decline in PACC, episodic memory (EM) and executive control (EC), in models adjusted by CSF biomarkers (Figure 2), and further modulated the association between CSF Aβ42/40 and PACC longitudinal decline (Figure 3) CONCLUSION: In CU individuals, CSF Aβ and p-tau affect RSFC in networks relevant for cognitive performance. Low CSF Aβ42/40 was related to hyperconnectivity between the DMN and the visual system. Lack of DMN segregation as a function of CSF Aβ42/40 may represent a driving mechanism of cognitive decline in the earliest Alzheimer's continuum.

PMID:39784371 | DOI:10.1002/alz.087302

Alzheimers Dement. 2024 Dec;20 Suppl 2:e084272. doi: 10.1002/alz.084272.

ABSTRACT

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 400x400 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: Figure 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. Figure 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.

PMID:39784322 | DOI:10.1002/alz.084272

Alzheimers Dement. 2024 Dec;20 Suppl 2:e091302. doi: 10.1002/alz.091302.

ABSTRACT

BACKGROUND: Previous cross-sectional studies have extensively documented that higher educational attainment (EA) is associated with lower β-amyloid (Aβ) plaques and tau tangles in Alzheimer's disease (AD). However, studies investigating the relationship between EA and longitudinal tau accumulation are strikingly lacking.

METHOD: We analyzed Aβ-PET (A), tau-PET (T), and 3D T1-MRI images (N) from the ADNI cohort to identify 196 Aβ-PET positive participants (A+) and 114 cognitively unimpaired participants without evidence of AD pathology and neurodegeneration (A-/T-/N-/CU). A subset of 209 individuals had resting-state functional MRI data (Rs-fMRI), and 173 participants had at least one follow-up tau-PET. Participants were categorized into High-Edu and Low-Edu subgroups based on the median years of education of the whole cohort (16 years). Aβ-PET SUVR of 18F-florbetapir (FBP) or 18F-forbetaben (FBB) were converted to Centiloids. Baseline and follow-up tau uptakes based on the Schaefer-200 atlas were compared between High-Edu and Low-Edu subgroups. The interaction of education status with baseline Aβ-Centiloids and entorhinal tau on longitudinal tau accumulation was assessed. The voxel-wise amplitude of low-frequency fluctuation (ALFF) and Regional Homogeneity (ReHo) maps calculated from Rs-fMRI data were compared between High-Edu and Low-Edu subgroups, and the impact of ALFF and ReHo alterations on Aβ-Centiloids and entorhinal tau-related longitudinal tau accumulation was also examined.

RESULT: A+ High-Edu individuals displayed lower baseline tau levels in temporal and parietal lobes but faster tau accumulation in medial and lateral temporal lobes (p<0.05, Figure 1). Moreover, A+ High-Edu individuals revealed more pronounced positive associations between Aβ-Centiloids and tau increases in bilateral visual cortices, as well as between entorhinal-tau and tau increases in inferior parts of temporal pole and middle temporal lobe, compared to Low-Edu individuals (p<0.05, Figure 2). Voxels with higher ALFF and ReHo in High-Edu individuals converged in a cluster in the temporal pole, and the higher ReHo of this cluster predicted faster entorhinal tau-related longitudinal tau accumulation in medial and lateral temporal cortices (p<0.05, Figure 3).

CONCLUSION: These findings suggest that higher EA is associated with faster tau accumulation in medial and lateral temporal lobes in AD, and the accelerated tau accumulation of these regions may be linked to higher ReHo associated with education.

PMID:39784238 | DOI:10.1002/alz.091302

Alzheimers Dement. 2024 Dec;20 Suppl 2:e089443. doi: 10.1002/alz.089443.

ABSTRACT

BACKGROUND: Higher order regulation of autonomic function is maintained by cortical and subcortical interconnected regions within the brain, collectively referred to as the central autonomic network (CAN) (Benarroch, 1993). Despite the well-established relationship between autonomic dysfunction and AD (Femminella et al., 2014) the relationship between CAN functional connectivity and biomarkers of AD, such as Ab42/40 ratio, remains unexplored.

METHODS: 76 independently living older adults were recruited from the community to undergo brain fMRI and venipuncture. Study exclusions were history of clinical stroke, dementia, major neurological or psychiatric disorder, current organ failure or other uncontrolled systemic illness. Resting state fMRI data were acquired and analyzed to quantify CAN functional connectivity from 3 previously described CAN networks with the CONN Functional Toolbox (Nieto-Castanon, 2020). Default mode network connectivity was also included for analysis as a negative control. Plasma Aβ40 and Aβ42 concentrations were obtained by digital immunoassay with the Simoa Neurology 3-Plex A (N3PA) Advantage Kit (Quanterix). Vascular risk factors were evaluated through interviews with the participant and informant, and included history of cardiovascular disease, hypertension, hyperlipidemia, type 2 diabetes, atrial fibrillation, and transient ischemic attack. The relationship between CAN functional connectivity and plasma Ab42/40 ratio was compared using linear regression adjusting for demographic covariates and vascular risk factor burden.

RESULTS: CAN functional connectivity was positively associated with Ab42/40 for all three CAN models (CAN A (Beissner et al., 2013) P= .0001; CAN B (Monroe et al., 2020) P= .018; CAN C (Riganello et al., 2018) P= .006), and remained so after adjustment for age, sex, and vascular risk factor burden. Default mode network connectivity was not significantly associated with Ab42/40 (Figure 1).

CONCLUSION: Older adults with decreased central autonomic network connectivity exhibit lower plasma Ab42/40, indicating greater cerebral Ab1-42 retention. This correlation could not be accounted for by age, sex, or vascular risk factor burden, suggesting a direct relationship between central autonomic function and cerebral amyloidosis. Further studies should explore the implications of CAN dysfunction for autonomic changes during the early stages of AD pathophysiology.

PMID:39784107 | DOI:10.1002/alz.089443

Alzheimers Dement. 2024 Dec;20 Suppl 2:e091552. doi: 10.1002/alz.091552.

ABSTRACT

BACKGROUND: Extracellular vesicles (EVs) are lipid bilayer nanoparticles (30-10,000 nm) released from all cells that facilitate cell-to-cell communication. Cell type-specific EVs can be enriched using cell-specific surface markers. Neuronal-enriched EVs (NEVs) contain measurable neurotrophins, pro- and mature brain-derived neurotrophic factor (BDNF), that have opposing action in neuronal plasticity. Exercise shifts the proBDNF/BDNF ratio toward BDNF, potentially enhancing brain health. This study investigates the relationship between NEV proBDNF/BDNF, Default Mode Network (DMN), and a BDNF polymorphism (Val66Met) in the context of the NIH-funded "Risk Reduction for Alzheimer's Disease" (rrAD) trial (NCT02913664).

METHOD: rrAD is a phase-II randomized controlled trial with banked plasma and neuroimaging from 512 cognitively normal subjects (ages 60-85, 34% aged 65-85) with a family history of Alzheimer's Disease (AD) and/or memory complaints. The 372 subjects that provided DNA consent were genotyped for Val66Met (Rs6265). EVs were isolated using ExoQuick followed by anti-NCAM-L1 immunoprecipitation and analyzed for size/concentration with a Zetaview NTA. Levels of proBDNF/BDNF protein were quantified by ELISA in baseline, 12, and 24-month plasma samples. MRI was performed on 3T scanners. Resting state functional (rs-f) MRI data was pre-processed using AFNI and ICA-based strategy was used for noise reduction.

RESULT: Of 372 consenting rrAD participants, 68% were Val/Val and 32% Met-carriers (Val/Met and Met/Met). Of Met carriers, 56% were male (sex vs. Met-carrier, P=0.33). A preliminary blinded cohort of EV isolation in n=21 subjects showed a substantial impact of BDNF Val66Met polymorphism on the proBDNF/BDNF ratio at baseline and 12 months. Higher BDNF in NEVs coincided with significantly stronger rs-fMRI connectivity in the ventral and dorsal DMN (P =0.02). However, the precise nature of this relationship and how it relates to rrAD intervention responses remains to be fully understood.

CONCLUSION: The study highlights the potential of BDNF polymorphisms in affecting the proBDNF/BDNF ratio and DMN activity, offering a valuable tool for disease prognosis and therapeutic effectiveness. It also suggests that AD trials need to account for BDNF polymorphisms to determine whether interventions aimed at slowing/preventing dementia are influenced by genetic factors and/or sex.

PMID:39784066 | DOI:10.1002/alz.091552