Most recent paper

Alzheimers Dement. 2024 Dec;20 Suppl 2:e084158. doi: 10.1002/alz.084158.

ABSTRACT

BACKGROUND: Women with suspected coronary microvascular dysfunction (CMD) may be at higher risk of experiencing cognitive decline due to cerebral small vessel disease, a known contributor to Alzheimer's disease and related dementias (ADRD). A potential underlying mechanism that could accelerate this cognitive decline is the accumulation of brain tissue iron, which has been previously linked to changes in brain function potentially caused by oxidative stress and cell death. Therefore, we aim to elucidate whether a similar mechanism could affect women with suspected CMD by investigating the potential role of iron deposition on the brain's functional organization and its effect on cognition using advanced magnetic resonance imaging (MRI).

MATERIAL AND METHODS: Twenty-seven women with suspected CMD [Age; median (range) = 54 (29-76)], drawn from ongoing cohorts (3R01HL146158-04S1,3U54AG065141-04S1), underwent a 3T MRI protocol, including submillimeter T2* 3-dimensional echo-planar-imaging for assessing iron deposition with high-resolution quantitative susceptibility mapping (QSM) and resting-state fMRI (rs-fMRI). Iron content was quantified by total-generalized-variation based QSM analysis. Functional integrity was determined via graph theoretical approach (i.e., nodal degree). Cognitive assessment was also performed using the NIH Toolbox. Mediation analysis was conducted using Python Statsmodels.

RESULTS: Most of the women with suspected CMD showed lower performance in processing speed, working memory, executive function, and attention (Figure 1A). We found a significant association between elevated iron levels in paracentral gyrus and lower functional connectivity in left hippocampus (p=0.005, adjusted-r2=0.19) (Figure 1B). Elevated iron level in the paracentral gyrus showed an impact on cognitive performance in the domains of executive function and attention (p<0.0001, coefficient=531.09) as well as language functions and crystalized abilities (p=0.036, coefficient=362.45), mediated by functional connectivity in the left hippocampus (indirect effect on executive function / language: p = 0.034 / 0.038, coefficient = -254.54 /- 213.06) (Figure 1C).

CONCLUSIONS: Our results suggest that changes in hippocampal functional organization are associated with cortical iron deposition and mediate its impact on cognitive performances. These changes may increase the risk of cognitive decline/ADRD or in women with suspected CMD. Future research in a larger cohort with a longitudinal design is necessary to validate and expand upon these findings.

PMID:39786148 | DOI:10.1002/alz.084158

Alzheimers Dement. 2024 Dec;20 Suppl 2:e090863. doi: 10.1002/alz.090863.

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) is associated with substantial synaptic loss potentially due to synaptotoxicity of fibrillar tau, but the association between tau deposition and synaptic loss remains unclear. Based on previous observations that pathology spreads preferentially between closely connected regions, we tested in the current multi-PET tracer study the hypothesis that synaptic loss propagates to regions closely connected to epicenters of high tau accumulation.

METHOD: We assessed 18F-SynVesT-1 PET as a measure of synaptic vesicle glycoprotein 2A (SV2A), and 18F-flortaucipir tau-PET in fourty-five 18F-florbetapir-PET-positive (Aβ+) subjects with MCI or AD dementia, and 23 cognitivly normal (CN) Aβ- controls. All PET scans were spatially normalized and parcellated into 200 ROIs. Adopting our previously established connectivity-based prediction model (Franzmeier et al. Nat Commun 2020), we computed tau-epicenter connectivity maps by projecting regions of highest tau-PET SUVR (top 10% of group-average tau-PET ROIs) onto a normative resting-state fMRI derived connectivity template from the Human Connectome Project. The tau-epicenter connectivity map was projected onto the group-average synaptic PET ROI w-scores (standardized SUVR difference between Aβ+ vs Aβ- group) to test in linear regression analysis, epicenter connectivity as a predictor of synaptic PET w-scores in connected ROIs. As a control, we conducted an additional regression analysis, using this time connectivity to cold spots of tau-accumulation (10% of ROI with lowest tau-PET uptake) instead of epicenter-connectivity as a predictor. We repeated the analyses at the subject level, controlling for the effect of age, gender, clinical diagnosis and global amyloid-PET uptake.

RESULT: Higher functional connectivity to the tau-epicenter was associated with lower synaptic PET binding in the connected ROIs (β = -0.380, p < 0.001, Figure 1A). In contrast, functional connectivity to the tau coldspot ROIs was associated with more preserved synaptic PET binding in the connected ROIs (β = 0.396, p < 0.001, Figure 1B). Subject-level analysis showed consistent findings (Figure 2 for tau-epicenters).

CONCLUSION: Synaptic loss in AD occurs in a connectivity-dependent manner, where closer functional connectivity to regions of high tau is associated with stronger loss in synaptic PET. Putative underlying mechanisms are the higher tau in tau-epicenter connected regions or functional decline in the connected regions.

PMID:39786129 | DOI:10.1002/alz.090863

Alzheimers Dement. 2024 Dec;20 Suppl 2:e091296. doi: 10.1002/alz.091296.

ABSTRACT

BACKGROUND: The posterior-medial network is crucial for episodic memory. However, the medial temporal lobe (MTL) and posteromedial cortex (PMC) regions are vulnerable to aging and early Alzheimer's disease (AD). Both processes might elicit distinct early functional connectivity (FC) changes which could be detrimental or protective/ compensatory regarding cognition. However, this is not well understood. We hypothesized that resting-state FC strength between key regions (Figure 1a) would decrease with age and memory decline without AD pathology (A-T-) but increase with early AD pathology.

METHOD: We analysed longitudinal 3-Tesla resting-state fMRI data from cognitively unimpaired older adults (OA; PREVENT-AD cohort). We assessed FC at baseline and after 24 months (FU24) in i) CSF or PET Aβ- and tau-negative OA (A-T-, N=96, 63±5years, 70 female, 28 APOE4) and ii) Aβ and p-tau CSF-characterized OA with available longitudinal p-tau181/Aβ1-42 ratio (N=65, 63±5years, 45 female, 22 APOE4). First, we investigated effects of age, APOE genotype and p-tau181/Aβ1-42 ratio on FC controlling for sex and education. Second, we tested the association between baseline FC or change in FC and change in delayed memory recall in multiple regression analyses.

RESULT: In A-T- OA, FC decreased mainly between regions within the PMC subnetwork over 24 months (Figure 1b). Higher baseline FCwithin-PMC was related to increasing memory performance over time (p = 0.047; Figure 2a). Longitudinally, increasing FCMTL-mPFC was associated with increasing memory in APOE4 non-carriers and decreasing memory in APOE4 carriers (p = 0.016; Figure 2b). In CSF-characterized OA, p-tau181/Aβ1-42 ratio at baseline and FU24 was related to increasing FCMTL-PMC over time (Figure 3a). Higher baseline FCMTL-PMC was associated with longitudinally increasing memory in APOE4 non-carriers and decreasing memory in APOE4 carriers (p = 0.028; Figure 3b).

CONCLUSION: Our results provide novel longitudinal evidence incorporating age, APOE, Aβ and tau indicating specific memory-related FC changes in cognitively unimpaired OA. APOE moderated the effects of FC strength on change in episodic memory performance. Higher FCMTL-PMC and increasing FCMTL-mPFC seem to be detrimental in APOE4 carriers but beneficial in APOE4 non-carriers. Importantly, this effect was observed in A-T- OA, hinting that APOE genotype may affect FC earlier than AD-related pathology.

PMID:39786103 | DOI:10.1002/alz.091296

Alzheimers Dement. 2024 Dec;20 Suppl 2:e090347. doi: 10.1002/alz.090347.

ABSTRACT

BACKGROUND: Memory decline in late life is a common hallmark of aging, yet SuperAgers are individuals age 80+ with episodic memory performances at least as good as cognitively average 50-to-60-year-olds. Recent work, combining anatomical and functional MRI, has shown the precise boundaries of large-scale resting state networks vary at the individual level. Further, the use of person-specific rather than standard parcellations has led to more behaviorally meaningful associations, and has not been explored in SuperAgers. The current project examines whether the topography of person-specific resting state networks differ between SuperAgers and older-aged controls (OACs).

METHODS: Twenty-four SuperAgers and 16 OACs were included in the study. SuperAger/OAC phenotype was determined based on measures of episodic memory, executive functioning, verbal fluency, and picture naming across two visits, separated by at least 18 months. Person-specific network parcellations were derived for each participant using their first visit resting state fMRI connectivity, constrained by anatomical priors, with a Multi-Session Hierarchical Bayesian Model (MS-HBM; Kong et al., 2021). Sørensen-Dice spatial similarity coefficients (Dice) were calculated to determine the within-group spatial similarity of each network. Dice was defined as the number of overlapping vertices between two participants' network segmentation, multiplied by two, and divided by the sum of vertices in both network segmentations. Dice was calculated for each participant compared to all other within-group participants and averaged to create a Dice score per participant per network. Dice scores for each of the 17 person-specific networks were compared between SuperAgers and OACs using Mann-Whitney tests, Bonferroni-corrected.

RESULTS: Demographics did not differ significantly between groups. Person-specific network topography varied between participants (Figure 1). SuperAgers had significantly lower Dice scores than OACs in six of 17 networks (Figure 2; p-value ≤ 0.0029).

CONCLUSION: Compared to OACs, SuperAgers demonstrated greater within-group variability in resting state network topography. Greater spatial variability may reflect unique patterns of functional or structural topography that support SuperAgers' exceptional memory abilities. Future investigations will include further examination of the functional connectome of SuperAgers, leveraging the precision approach employed here.

PMID:39786048 | DOI:10.1002/alz.090347

Alzheimers Dement. 2024 Dec;20 Suppl 2:e088546. doi: 10.1002/alz.088546.

ABSTRACT

BACKGROUND: Social cognition is impacted early in the disease progression of many neurodegenerative diseases (ND). The Salience network (SN) is an intrinsically connected brain network responsible for social cognitive function. Keys hubs of this brain network, the anterior insula (AI) and anterior cingulate cortex (ACC), are reported to incorporate 'bottom-up' signals from subcortical regions such as the amygdala and periaqueductal gray (PAG), but this mechanism and the subcortical contribution to SN connectivity is poorly understood. Our aim was to investigate the contribution of cortical and subcortical structures to SN functional connectivity and to social cognition across NDs.

METHOD: 76 participants (21 Alzheimer's disease, 13 behavioural variant frontotemporal dementia, and 42 Parkinson's disease) from the Ontario Neurodegenerative Research Initiative (ONDRI) baseline or one-year follow up visits with resting state fMRI, Montreal Cognitive Assessment (MoCA) total scores, and informant-reported socioemotional sensitivity scores using the Revised Self-Monitoring Scale (RSMS) were included (higher score, indicating higher function). All groups were age- and sex-matched. Fisher-transformed correlation coefficients of functional connectivity from an ROI-to-ROI analysis between cortical and subcortical SN ROIs were used to create a mean cortical SN value and mean subcortical SN value to use in linear regression modelling with behavioural scores.

RESULT: Mean cortical and subcortical SN connectivity were significantly associated with RSMS total score (b = 2.94, p = 0.041; (b = 3.60, p = 0.014, respectively), independent of cognitive function, with higher connectivity predicting higher score. The interaction between cortical and subcortical connectivity was not significantly associated with RSMS total score. Mean cortical and subcortical connectivity was significantly associated with RSMS-EX (expressive behaviour of others) and RSMS-SP (self-presentation) subscores (b = 1.36, p = 0.049; b = 1.44, p = 0.040; b coef = 1.58, p-value = 0.033; b coef = 2.15, p-value = 0.005, respectively).

CONCLUSION: Our results indicate a stronger contribution of subcortical structures to social cognition-related functional connectivity across various neurodegenerative diseases. Despite previous associations with cortical regions, our evidence suggests that alterations in subcortical structures mediate changes in social cognition. Further exploration in larger cohorts is necessary, as impaired social cognition in patients with ND is associated with increased caregiver distress.

PMID:39786018 | DOI:10.1002/alz.088546

Alzheimers Dement. 2024 Dec;20 Suppl 2:e088708. doi: 10.1002/alz.088708.

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) is defined by the accumulation of Aβ plaques and tau neurofibrillary tangles. The consequences of these pathologies include neurodegeneration and cognitive dysfunction. However, the process by which AD pathologies leads to cognitive impairment remains unclear. Some individuals can harbor pathological burden yet be cognitively unimpaired; these observations have led to ideas about cognitive reserve (Stern, Lancet, 2012). Dominant models of AD biomarkers do not include direct measures of brain function. To address this gap, we tested whether resting-state brain system segregation explains discrepancies between AD-related pathology, structural atrophy, and cognitive function. System segregation changes across the adult lifespan, is stratified in relation to life course exposures, and relates to cognitive function (Wig, Trends in Cognitive Sciences, 2017).

METHOD: Participants were recruited through the Alzheimer's Disease Neuroimaging Initiative. Cognitive impairment was quantified using clinical dementia rating (CDR). The participant group included 184 healthy (CDR=0) adults, 101 very mild dementia (CDR=0.5), 24 mild dementia (CDR=1) and 2 moderate dementia (CDR=2) patients (age range: 55-96 years). Functional brain networks were generated using resting-state fMRI time series. Network edges were defined as correlations between time series of each pair of nodes. Brain system segregation was calculated to quantify functional brain network organization for each participant (Chan et al., PNAS, 2014).

RESULT: Multiple linear regression analyses were used to test whether Aβ and tau relate to brain system segregation, with age, gender, education, and head motion included as covariates. Neither Aβ nor tau burden was associated with brain system segregation (Aβ: p=0.45; tau: p=0.55). Among individuals exhibiting positive pathological burden (either Aβ, tau, or both) based on cut-off values, individuals with higher system segregation were less cognitively impaired (Aβ+: p=0.007; tau+: p=0.021; Aβ and tau+: p=0.03). Finally, system segregation explained unique variance with respect to CDR status over and above Aβ, tau, and cortical thickness. Brain system segregation was negatively related to CDR status (p=0.003), while accounting for these other factors.

CONCLUSION: Functional brain network organization supports observations of cognitive reserve, and explains unique variance with respect to AD-related cognitive impairment independent of AD-related pathology and neurodegeneration.

PMID:39786015 | DOI:10.1002/alz.088708

Alzheimers Dement. 2024 Dec;20 Suppl 2:e087406. doi: 10.1002/alz.087406.

ABSTRACT

BACKGROUND: Recent advancements in connectome analyses allow for more fine-grained measurements of brain network integrity. One measure of integrity is resilience, or the capacity of the network to retain functionality when confronted with endogenous or exogenous perturbations that result in damage or error. We assessed the impact of individual differences in the resilience of resting BOLD connectivity on the relationship between cognitive and brain changes in a lifespan cohort of cognitively healthy adults over a 5-year period.

METHOD: One hundred twenty-six cognitively healthy participants from the Reference Ability Neural Network (RANN) longitudinal lifespan cohort (age 20-80 years) underwent resting-state fMRI to measure functional connectivity and an out-of-scanner neuropsychological battery at baseline and five-year follow-up. Undirected weighted adjacency matrices were generated from Schaefer et al. (2018) 400 parcellation atlas. As a measure of whole-brain network resilience, we adopted a targeted attack approach, whereby nodes are sequentially removed from the connectome in order of nodal strength. At each iteration of attack, nodal strength is recalculated based on the effect of prior lesioning and the largest connected component (LCC) is measured. We inferred that more resilient individuals will sustain larger LCCs over longer iterations of lesioning before decay in LCC becomes evident, with resilience operationalized as the iteration of steepest slope in LCC.

RESULT: We tested whether our operationalization of brain resilience (BR) moderated the effect of brain integrity (i.e., cortical thickness; CT) on out-of-scanner neuropsychological test performance across four domains of cognition in the context of longitudinal change (∆) over time. After accounting for baseline differences in change variables and adjusting for the demographic factors of Age, Sex, NART IQ, and Education, we observed a significant negative interaction between ∆CT and ∆BR on ΔCognition for the Fluid Reasoning domain. That is, individuals with increased brain resilience over time were less sensitive to the effect of changes in cortical thickness on changes in cognition.

CONCLUSION: Our finding supports evidence for targeted attack as a measure of cognitive reserve, where higher brain network resilience may have permitted individuals with reduced brain integrity to better cope with structural loss and enhance preservation of cognitive function.

PMID:39785979 | DOI:10.1002/alz.087406

Alzheimers Dement. 2024 Dec;20 Suppl 2:e092515. doi: 10.1002/alz.092515.

ABSTRACT

BACKGROUND: AD is defined by cortical amyloid-β (Aβ), tau neurofibrillary tangles, and neurodegeneration, pathological processes which may contribute to cognitive decline by altering large scale functional brain networks. To test this hypothesis, we examined whether plasma biomarkers of AD pathology (Aβ42/40, phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) related to longitudinal changes in resting-state functional connectivity (rsFC) in cognitively unimpaired participants from the Baltimore Longitudinal Study of Aging.

METHOD: Baseline plasma biomarkers were measured with Quanterix SIMOA assays. Functional connectivity (3T resting-state fMRI) was derived using a predefined cortical parcellation mask from which intra-network connectivity from seven functional networks was extracted for each participant. Amyloid status (positive/negative) was defined using plasma Aβ42/40 (Figure 1). Linear mixed effects models adjusted for age, sex, race, education, gray matter volume, and time-covariate interactions were used to determine whether 1) baseline plasma biomarkers predicted longitudinal changes in rsFC, 2) the magnitude of the biomarker-related rsFC changes differed by amyloid status, and 3) rsFC predicted longitudinal changes in cognition.

RESULT: Longitudinal connectivity analyses (mean age±SD=65.49±16.17) included 490 participants (1190 visits; mean follow-up time=4.31±1.68 years). Higher Aβ42/40, GFAP, and NfL were associated with faster declines in rsFC within several networks (P-range=0.01-0.04; Figure 2). Overall, plasma biomarker-rsFC associations differed by amyloid status (P-range=0.01-0.045). Among amyloid-positive participants, lower levels of Aβ42/40, and higher levels of GFAP, and NfL (Figure 2) were associated with faster declines in rsFC in the visual, dorsal and ventral attention, limbic, and frontoparietal networks (P range=<0.002-0.04). There were no statistically significant associations between plasma biomarkers and rsFC change among amyloid-negative participants. Among 760 participants with at least one rsFC scan (mean age±SD=67.21±14.93; 1550 visits, follow-up time=3.94±1.60 years), we found that baseline rsFC in several networks predicted changes in cognition, e.g., working memory, verbal fluency, and visuospatial abilities (P range=0.02-0.049; Figure 3).

CONCLUSION: Among cognitively normal individuals, plasma biomarkers of Aβ42/40, astrogliosis, and neuronal injury are associated with future intra-network functional brain changes, particularly in the context of elevated amyloid. Hypo- and hyper- intra-network connectivity may drive changes in cognitive performance.

PMID:39785944 | DOI:10.1002/alz.092515

Alzheimers Dement. 2024 Dec;20 Suppl 2:e092805. doi: 10.1002/alz.092805.

ABSTRACT

BACKGROUND: Hemodynamic signals are the basis of functional brain imaging techniques, such as fMRI and NIRS, and are often used to infer changes in resting-state functional connectivity (RSFC) in Alzheimer's disease (AD) and other dementias. Increasing evidence suggests that disruption of neuronal circuits has been associated with the AD continuum and may precede changes in Ab and tau biomarkers, neurodegeneration, and cognitive impairment. To better understand the changes in brain RSFC through the AD spectrum, we use hemodynamic signals to detect disease onset, progression, and response to therapy in a mouse model of AD.

METHOD: Hemodynamic signals were recorded longitudinally (3-8 months) in anesthetized (ketamine/xylazine) and awake WT and APP (J20) mice, implanted with full cranial window, using optical imaging of intrinsic signals (OIS), together with cognitive testing. Seed-based functional connectivity maps were generated for the bilateral connectivity (BC) and RSFC analyses. The effects of simvastatin (SV), a cardiovascular medicine that has shown promise in preventing dementia, were evaluated after 2.5 and 5 months.

RESULT: Alterations in RSFC in brain regions associated with the sensory-motor (SM) and default-mode (DMN) networks were detected before the appearance of cognitive impairment. 3-month-old APP mice showed consistent decrease in bilateral functional connectivity (BC) in motor (M) and cingulate (C) cortical regions and a severe hypoconnectivity within the SM network in the RSFC analysis. Throughout the course of the disease, RSFC analysis in APP mice uncovered an early hyperconnectivity within the DMN, mainly driven by the frontal (F) cortex, followed by a later hypoconnectivity stage. At late stage of the disease (8-months-old), a decreased BC in somatosensory (S) cortex was detected. SV treatment prevented the aberrant increases in DMN FC in midlife APP mice, improved the BC of S cortex, while concurrently sparing cognitive function.

CONCLUSION: Our results demonstrated that hemodynamic signals measured by OIS at the cortical level successfully detected RSFC disruptions preceding dementia in APP mice and allowed to capture SV therapeutic benefits. These findings suggest that OIS, or its human equivalent NIRS, could contribute to effectively diagnosing the early stages of AD, leading to promising intervention opportunities.

PMID:39785918 | DOI:10.1002/alz.092805

Alzheimers Dement. 2024 Dec;20 Suppl 2:e092741. doi: 10.1002/alz.092741.

ABSTRACT

BACKGROUND: Clinicians and researchers utilize neuroimaging (NI) biomarkers of Alzheimer's disease (AD) at an increasing rate. It is crucial that we determine whether these biomarkers generalize to underrepresented populations, particularly Black Americans (BAs), as they are 64% more likely as white individuals to develop AD. BAs may exhibit unique AD biomarker profiles across disease states, including NI biomarkers. Investigating biomarkers in at-risk individuals may allow for early identification and intervention. Here we analyze comprehensive NI biomarkers including resting state fMRI, white matter lesions, and hippocampal volumes in conjunction with cerebrospinal fluid (CSF) markers in a midlife, racially diverse, cognitively normal cohort with a parental history of AD.

METHOD: Data included 57 cognitively normal, middle-aged individuals, 14 BAs and 43 white. CSF was acquired via lumbar puncture to determine CSF t-tau and Aβ1-42 concentrations. Using resting state fMRI data, we analyzed default mode network connectivity between the posterior cingulate & precuneus, parrahippocampal gyrus (PHG), temporal pole, hippocampus, and lateral temporal cortex. We obtained regional WMH data from FLAIR images using an in-house algorithm, and hippocampal volumes from Freesurfer. In our multivariate model, outcome variables were connectivity values, regional WMH and hippocampal volumes, with race and CSF t-tau and Aβ1-42 as our independent variables with a race X CSF interaction term.

RESULT: We identified a significant race X t-tau and race X Aβ1-42 interaction term for temporal and parietal WMH volumes and connectivity between PHG and temporal pole. Higher AD CSF biomarkers negatively correlated with brain connectivity (p=0.01), and positively with WMH volume (p<0.001) in BAs.

CONCLUSION: We extend our previous work to a middle-aged cohort to show that DMN connectivity may be a predictor of AD risk in middle-age, particularly for BAs, and that BAs may exhibit earlier vulnerability to vascular lesions. We support previous work that the temporal lobe is the first region to experience AD-related connectivity changes, and that WMHs may predispose this region to AD vulnerability. This study emphasizes the need for recruitment of diverse cohorts in NI studies of AD.

PMID:39785910 | DOI:10.1002/alz.092741

Alzheimers Dement. 2024 Dec;20 Suppl 2:e085783. doi: 10.1002/alz.085783.

ABSTRACT

BACKGROUND: Progressive supranuclear palsy (PSP) can present with different clinical variants which show distinct, but partially overlapping, patterns of neurodegeneration and tau deposition in a PSP network of regions, including cerebellar dentate, superior cerebellar peduncle, midbrain, thalamus, basal ganglia, and frontal lobe. We sought to determine whether disruptions in functional connectivity within this PSP network measured using resting-state functional MRI (rs-fMRI) differed between PSP-Richardson's syndrome and the cortical and subcortical variants of PSP.

METHOD: Structural MRI and rs-fMRI scans were collected for 40 PSP-RS, 24 PSP-cortical (12 speech and language; 10 corticobasal syndrome; 2 frontal) and 36 PSP-subcortical (18 parkinsonism; 11 progressive gait freezing; 6 postural instability; 1 oculomotor) participants who met the Movement Disorder Society PSP clinical criteria (Table 1). Ninety-six participants underwent flortaucipir-PET scans. MRIs were processed using CONN Toolbox. Functional connectivity between seeds placed throughout the PSP network was compared between each PSP group and 83 healthy controls, and between the PSP groups, covarying for age and sex.

RESULTS: Connectivity was reduced throughout the network in PSP-RS compared to controls (Figure 1A), involving cerebellar dentate, midbrain nuclei, subthalamic nuclei, basal ganglia, thalamus, and frontal regions. Frontal regions showed reduced connectivity to other regions in the network in PSP-cortical, including substantia nigra and superior cerebellar peduncle. Disruptions in connectivity in PSP-subcortical were less pronounced, with the strongest disruption between the pallidum and putamen. When PSP groups were compared to each other (Figure 1B), PSP-RS had lower connectivity from the thalamus and cerebellar dentate to the cortex compared to PSP-subcortical and from the thalamus to substantia nigra than PSP-cortical. PSP-subcortical had lower connectivity from the subthalamic nucleus to caudate than PSP-RS and from the subthalamic nucleus to substantia nigra than PSP-cortical and higher connectivity from the thalamus to the prefrontal cortex than both the other variants. Voxel-based analyses replicated these patterns. There was moderate evidence that tau uptake in the PSP network regions influenced connectivity between these regions in PSP.

CONCLUSIONS: Patterns of disrupted functional connectivity revealed both variant-specific and shared disease pathways among PSP variants, providing insight into the disease heterogeneity beyond patterns of atrophy.

PMID:39785752 | DOI:10.1002/alz.085783

Alzheimers Dement. 2024 Dec;20 Suppl 2:e085547. doi: 10.1002/alz.085547.

ABSTRACT

BACKGROUND: Synaptic loss is identified as a strong correlate of cognitive impairment in Alzheimer's disease (AD). Pathological tau can induce direct toxicity to synapse and spread trans-synaptically across connected neurons. Recent neuroimaging evidence revealed that tau pathology propagates along interconnected brain regions throughout macroscale brain networks. However, whether synaptic loss propagates in AD follows a similar vein is unclear.

METHOD: Seventy-six amyloid-positive (Aβ+) subjects across AD spectrum and 48 cognitively normal (CN) Aβ- controls characterized by cross-sectional [18F]florbetapir amyloid-PET were included in the current study. The density of synaptic vesicle glycoprotein 2A (SV2A) was measured by [18F]SynVesT-1 PET. A normative template of functional connectome distance across 200 neocortical regions of interest (ROIs) was generated using resting-state fMRI data from 1000 subjects of the Human Connectome Project. We assessed the association between synaptic loss and functional connectivity by correlating the cross-subject inter-regional covariance with the normative functional connectivity template. In a next step, we tested whether the functional distance to synaptic loss epicenter (i.e., top 10% ROIs with greatest synaptic loss) is associated with synaptic loss in connected regions at both group- and subject-level.

RESULT: Among Aβ+ subjects, inter-regional covariance of SV2A-PET-assessed synaptic loss was associated with inter-regional functional connectivity (Figure 1), suggesting that higher functional connectivity may facilitate the propagation of synaptic loss. At both group- and subject-level, we found that shorter functional distance to synaptic loss epicenters is associated with greater levels of synaptic loss in connected regions (Figure 2).

CONCLUSION: We found that inter-regional functional connectivity is associated with greater synaptic loss in AD, suggesting that synaptic loss may systematically propagate along brain connections.

PMID:39785750 | DOI:10.1002/alz.085547

Alzheimers Dement. 2024 Dec;20 Suppl 2:e086417. doi: 10.1002/alz.086417.

ABSTRACT

BACKGROUND: Dementia, particularly Alzheimer's disease (AD), is a significant public health concern, with midlife emerging as a critical period for preventive intervention (Livingston, 2017). Dementia's heterogeneity renders single risk factor insufficient for accurate identification of individuals at risk (Stephen, 2021). Multifactorial risk scores, such as the cardiovascular risk factors, aging, and dementia (CAIDE) score (Kivipelto, 2006), which include both cardiovascular (blood pressure, cholesterol, BMI, physical inactivity) and non-modifiable factors (age, sex, APOE ε4 genotype), are vital in assessing dementia risk. This study, using the network-based statistic (NBS)-Predict model (Serin, 2021), aimed to explore the functional brain architecture associated with these risk factors, aiding in personalized prevention and intervention strategies for dementia.

METHOD: Resting-state fMRI data, CAIDE, cardiovascular and non-modifiable risk scores, and lifetime of experiences questionnaire (LEQ) data were analyzed from 585 healthy participants (females/males=207/378, mean age=50.9) in the PREVENT-Dementia study (Ritchie, 2023). Using the Dosenbach atlas, functional connectivity (FC) matrices were constructed post-data preprocessing. The NBS-Predict model, employing a linear support vector machine with 10-fold cross-validation, feature selection at p<0.05, and 1000 permutations, predicted CAIDE, cardiovascular, and non-modifiable risk scores (Figure 1). A hierarchical regression model assessed the impact of midlife LEQ score on FC linked to cardiovascular risk factors, with LEQ scores, age, sex, education years, and mean framewise displacement as independent variables.

RESULT: NBS-Predict models significantly predicted the CAIDE (r=0.214, p<0.001), cardiovascular (r=0.201, p<0.001), and non-modifiable (r=0.237, p<0.001) risk factors scores. Similar FC patterns were observed between the CAIDE and cardiovascular risk scores, particularly involving the somatomotor and cingulo-opercular networks (Figure 2a), contrasting with distinct patterns for non-modifiable risk factors. The non-specific LEQ score positively correlated with FC in regions affected by cardiovascular risk factors (β=0.001, p=0.017).

CONCLUSION: The study demonstrated a significant overlap in FC patterns between CAIDE and cardiovascular risk factors in midlife, distinct from patterns associated with non-modifiable risk. This suggested different neurobiological pathways influencing dementia risk in midlife, emphasizing the importance of personalized dementia prevention strategies. The findings highlighted the positive impact of an active and engaged lifestyle on brain health, reinforcing the need for early intervention targeting cardiovascular health for dementia risk reduction.

PMID:39785745 | DOI:10.1002/alz.086417

Alzheimers Dement. 2024 Dec;20 Suppl 2:e085546. doi: 10.1002/alz.085546.

ABSTRACT

BACKGROUND: In Alzheimer's disease, Aβ triggers tau spreading which drives neurodegeneration and cognitive decline. However, the mechanistic link between Aβ and tau remains unclear, which hinders therapeutic efforts to attenuate Aβ-related tau accumulation. Preclinical research could show that tau spreads across connected neurons in an activity-dependent manner, and Aβ was shown to trigger neuronal hyperactivity and hyperconnectivity. Therefore, we hypothesized that Aβ induces neuronal hyperactivity and hyperconnectivity, thereby promoting tau spreading from initial epicenters across connected brain regions.

METHODS: From ADNI, we included 140 Aβ-positive subjects across the AD spectrum plus 69 Aβ-negative controls, all with baseline amyloid-PET, 3T resting-state fMRI and longitudinal Flortaucipir tau-PET data. For validation, we included cross-sectional tau-PET, amyloid-PET and resting-state fMRI data of 345 preclinical AD patients from A4. PET and fMRI data were parceled into 200 cortical ROIs, ROI-wise longitudinal tau-PET change rates were computed using linear mixed models. Resting-state fMRI connectivity was computed across the 200 ROIs. Subject-specific tau epicenters were defined as 5% of ROIs with highest baseline tau-PET. Further, we included post-mortem brain tissue from 5 AD patients vs. 4 controls stained for Aβ and c-Fos, i.e. a marker of ante-mortem neuronal activity.

RESULTS: In the AD spectrum cohort, we confirmed that Aβ induces hyperconnectivity of temporal lobe tau epicenters (Figure 1) to posterior brain regions that are highly vulnerable to tau accumulation in AD (Figure 2A-C). This was fully replicated in the validation cohort of preclinical AD patients with low cortical tau-PET, suggesting that the emergence of Aβ-related hyperconnectivity precedes neocortical tau spreading (Figure 2D). Supporting that Aβ-associated fMRI-based hyperconnectivity may mirror neuronal hyperactivity, we found that neurons in AD post-mortem tissue expressed higher levels of c-Fos compared to controls, i.e. a Calcium-sensitive marker of ante-mortem neuronal activity (Figure 3). Lastly, using longitudinal tau-PET, we confirmed that Aβ-related connectivity increases of the tau epicenters to posterior brain regions mediated the effect of Aβ on tau accumulation and triggered faster tau spreading (Figure 4).

CONCLUSIONS: Our translational results suggest that Aβ promotes tau spreading via increasing neuronal activity and connectivity. Therefore, Aβ-associated neuronal hyperexcitability may be a promising target for attenuating tau spreading in AD.

PMID:39785719 | DOI:10.1002/alz.085546

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