Most recent paper

Public Health

Thu, 01/09/2025 - 19:00

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

Public Health

Thu, 01/09/2025 - 19:00

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

Biomarkers

Thu, 01/09/2025 - 19:00

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

Biomarkers

Thu, 01/09/2025 - 19:00

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

Biomarkers

Thu, 01/09/2025 - 19:00

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

Biomarkers

Thu, 01/09/2025 - 19:00

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

Biomarkers

Thu, 01/09/2025 - 19:00

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

Biomarkers

Thu, 01/09/2025 - 19:00

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

Biomarkers

Thu, 01/09/2025 - 19:00

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

Biomarkers

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 2:e091808. doi: 10.1002/alz.091808.

ABSTRACT

BACKGROUND: States of altered metabolic health such as metabolic syndrome (MetS), obesity, and insulin resistance increase Alzheimer's Disease (AD) risk. Individuals with these conditions, like those with AD, have demonstrated changes in the structural and functional features of the Default Mode Network (DMN). Here, we characterize associations between systemic metabolic dysfunction, brain structure (Cortical Thickness and Hippocampal Volume) and functional connectivity of DMN subnetworks.

METHOD: We leveraged data from the Health and Aging Brain Study: Health Disparities (HABS-HD) dataset, an ongoing longitudinal study that characterizes AD biomarkers across diverse populations. Specifically, we used data from the initial visits of the Hispanic and Non-Hispanic White (NHW) cohorts. Individuals were categorized as cognitively healthy (n=1192; age=66.1 years, 65% female) or cognitively impaired (n=307; age=67.4 years, 50% female). We used a continuous measure of metabolic risk (Mets-Z) that is more sensitive and ethnicity-specific than categorical definitions of MetS. Mets-Z a weighted composite of systolic blood pressure, triglycerides, HDL cholesterol, glucose, and waist circumference. Structural measures were acquired using FreeSurfer. Functional connectivity was measured via resting-state fMRI, and pre-processed using FSL. We utilized both summary metrics (ROI-based connectivity estimations) and voxel-wise approaches (FSL's randomise).

RESULT: MetS-Z differed between diagnostic groups (t=-2.387, p=.017) and between Hispanics and NHWs (t=-11.864, p<.001). Meta-ROI cortical thickness was negatively associated with both cognitive status (β = -.152, p < .001) and MetS-Z (β = -.085, p < .001). Hippocampal volume was found to have a negative relationship with MetS-Z (left, β = -.073, p < .001; right, β = -.072, p < .001). Functional connectivity, specifically of the posterior DMN, was significantly associated with MetS-Z. There was a high degree of overlap between the clusters of voxels in which MetS-Z and pDMN connectivity associated, and the clusters demonstrating decreased connectivity to due to age and cognitive status.

CONCLUSION: We present evidence of altered DMN connectivity due to a higher load of metabolic risk in an ethnoracially diverse cohort of older adults, with and without cognitive impairment. Future studies should leverage the longitudinal HABS-HD dataset to examine if higher metabolic dysfunction predicts differences in the trajectory of DMN connectivity.

PMID:39784030 | DOI:10.1002/alz.091808

Biomarkers

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 2:e093543. doi: 10.1002/alz.093543.

ABSTRACT

BACKGROUND: Mild cognitive impairment(MCI) is characterized by an impairment in one or more cognitive domains greater than expected for a person's age and educational background with preserved functional independence. Functional Near Infra-Red Spectroscopy (fNIRS) is a modality of non-invasive neuroimaging that utilizes the optical properties of oxygenated and deoxygenated hemoglobin in the tissue to measure their absolute or relative concentrations following neuronal activity. fNIRS has been used to evaluate neurohemodynamics in MCI. Lower tissue oxygenation in bilateral frontal and parietal regions was found at resting state, which correlated with cognitive functioning in MCI. The objective of this study was to evaluate the correlation between cognitive functioning and resting state functional connectivity on fNIRS in MCI.

METHODS: The study was conducted at the Geriatric Clinic and Services, Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India (Institutional Ethics Committee approval no.: NIMHANS/34th IEC (BEH.SC.DIV.)/2022) on consenting participants with MCI (N = 38). Detailed cognitive assessment was performed using a validated comprehensive computerised cognitive battery. fNIRS data acquisition was done using the NIRScout device, NIRx medical technologies LLC, CA, USA, operating on continuous wave domain, with two wavelengths of 760nm and 850 nm. 8 sources and 8 detectors were placed in a bilateral prefrontal montage placement resulting in 18 channels (9 on each side). Nodal metrics such as clustering coefficient, degree centrality, shortest path length, local efficiency and a Global metric- small worldness was evaluated. Correlation coefficients were computed for the nodal and global metrics with cognitive domains such as reaction time, complex attention, memory, language functioning and perceptuomotor functioning.

RESULTS: Mean age of participants was 66.18 ± 6.18 years. The mean duration of illness was 2.63 ± 2.5 years. The results of the resting state nodal and global metrics and their correlation with cognitive functioning will be presented during the conference.

CONCLUSION: fNIRS is reported to have a temporal resolution that is comparable to fMRI, at the same time being less expensive, portable and having less interference because of motion artifacts. Findings from this study will provide insights on the functional connectivity correlates of cognitive functioning in MCI.

PMID:39783936 | DOI:10.1002/alz.093543

Biomarkers

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 2:e093549. doi: 10.1002/alz.093549.

ABSTRACT

BACKGROUND: Previous work suggests functional abnormalities in the human brain in preclinical Alzheimer's disease. However, little has been explored about the relationship between BOLD fMRI signal amplitude/energy over time and AD pathology. In this work we analyzed the effects of AD progression on amplitude of low-frequency fluctuations (ALFF) during resting-state fMRI scans both at the whole-brain level and at a more granular level, focused on regions of the medial temporal lobe (MTL) that are most vulnerable to AD pathology.

METHOD: In this cross-sectional study, we analyzed data from 224 individuals from the Penn ADRC cohort (Table 1). All participants underwent structural and functional MRI on a Siemens 3T Prisma system, and 18F-Florbetaben or 18F-Florbetapir amyloid-PET imaging. 125 participants also underwent 18F-Flortaucipir tau-PET scans. Functional images were preprocessed using a custom implementation of fMRIprep and ALFF was extracted using Conn software. In the whole-brain analyses we performed voxelwise GLMs with age and sex as covariates.

RESULTS: We observed reduced ALFF in both preclinical AD (Amyloid-positive (Aβ+) cognitively unimpaired, CU) and Aβ+ cognitively impaired (CI) individuals. Relative to Aβ- controls, individuals with preclinical AD displayed lower ALFF in frontal, parietal and temporal association cortices (Figure 1, top left). CI individuals displayed lower ALFF in most of the brain, except in inferior temporal cortex, temporal pole, and MTL. The effect of AD progression on ALFF was characterized by a progressive reduction primarily in frontal and parietal regions that roughly align with the anatomy of the default mode network. In contrast, transentorhinal tau pathology was negatively associated with ALFF in frontal and anterior temporal lobes, as well as insula and MTL (Figure 1 bottom right). Negative association between tau burden and MTL ALFF was observed in all main MTL subregions, and strongest in the transetorhinal cortex (Figure 2).

CONCLUSION: We conclude that: (1) ALFF might be a promising biomarker for studying functional abnormalities in preclinical AD, and (2) based on the spatial topography of amyloid and tau effects on ALFF (Figure 1 bottom), there is likely a differential effect of of the two on ALFF that needs to be further explored.

PMID:39783906 | DOI:10.1002/alz.093549

Developing Topics

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095158. doi: 10.1002/alz.095158.

ABSTRACT

BACKGROUND: We aim to describe the imaging findings in pre-symptomatic and early-symptomatic individuals carrying a recently described novel APP duplication rearrangement causing early-onset AD (EOAD).

METHOD: We studied individuals from one pedigree that carry APP duplication and CH 5 mutation gain that had structural and resting state functional (rs-f) brain MRI. Non-carrier family members were assessed as controls. Volumetric analysis was performed using Freesurfer and normalized to total intracranial volume. Fazekas scores for white matter hyperintensities (WMH) and microbleed count were performed visually by two neuroradiologists. rs-fMRI seed to whole brain analysis was used to create functional connectivity maps of the default mode network (DMN). F18-Flutemetamol amyloid-PET was available for two of the mutation carriers. Amyloid deposition was quantified using SUVR with the pons as reference region and compared to SUVR of young adults and amyloid-positive older adults (Ab+OA).

RESULT: Fourteen mutation carriers (mean age 29.8[19-39], 8 (57%) F, median education 12Y[11-14Y], mean MMSE 28[23-30]), and nine non-carrier family members were included (36.8Y[19-56Y], 5 (55%)F, 12Y[12-19], 29[27-30]). Volumetric analysis revealed an increase in amygdala volume (log) (estimate = 0.01, p = 0.03) and a (non-statistically significant) trend toward decrease in the putamen, globus pallidus, and pons volume with age in mutation carriers (Figure 1A). WMHs and microbleeds were found in some mutation carriers from the age of 28Y (Figure 1B). rs-fMRI showed a trend toward a disconnection between the anterior and the posterior component of the DMN in the APP-dup carriers >30Y (n = 6) compared with non-carrier (n = 8; U = 10, p = 0.08). Moreover, increased connectivity was found between the anterior component of the DMN and the striatum compared to carriers <30Y (n = 8, U = 9, p = 0.06) and to non-carriers (U = 9, p = 0.06) (Figure 2). Cortical amyloid deposition was high but within the range of Ab+OA, and extremely high, above the level of deposition in Ab+OA in the putamen, caudate, and thalamus (Figure 3).

CONCLUSION: We found early basal ganglia abnormalities in presymptomatic and early symptomatic novel APP duplication mutation carriers, including high amyloid deposition, DMN disconnection, increased connectivity between anterior DMN and striatum, and volumetric alterations. These findings point to the basal ganglia as a region of early pathology that requires further research.

PMID:39783581 | DOI:10.1002/alz.095158

Developing Topics

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 8:e094898. doi: 10.1002/alz.094898.

ABSTRACT

BACKGROUND: As of 2024, an estimated 6.9 million individuals reside in the United States with Alzheimer's Disease (AD). Previous studies suggest that AD disproportionately affects females, who exhibit a higher incidence rate, poorer performance on various neuropsychological tasks, and more significant total brain atrophy. Recent investigations reveal differences in hippocampal functional connectivity based on sex, potentially contributing to the observed sex-related disparities in AD. Moreover, individuals carrying higher levels of the tau protein show reduced hippocampal functional connectivity.

METHOD: Using Resting State fMRI and T2 MRI data from participants with AD (n = 20, female = 9) and cognitively normal individuals (n = 20, female = 9) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we employed the Functional Connectivity Toolbox (CONN) for analysis.

RESULT: Our findings revealed differences in hippocampal functional connectivity between individuals with higher and lower levels of plasma NT1-tau levels in each group. Additionally, sex differences in hippocampal functional connectivity were observed among AD participants with higher tau protein levels.

CONCLUSION: These results enhance our understanding of the complex interplay between sex, tau levels, and hippocampal function in AD. Such insights into biomarkers may inform the development of sex-specific interventions aimed at enhancing AD treatment efficacy.

PMID:39783476 | DOI:10.1002/alz.094898

Developing Topics

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 8:e094926. doi: 10.1002/alz.094926.

ABSTRACT

BACKGROUND: Changes in brain functional connectivity obtained from resting state MRI (rs-fMRI) have been found to be associated with cognitive decline and neurodegeneration in clinical trial participants with Alzheimer's disease (AD). This study investigates whether and how this technique can be used in AD clinical trials to monitor treatment effects. Specifically, we analyzed changes in brain functional connectivity over a period of 116 weeks in participants with AD treated with gantenerumab, an investigational anti-amyloid beta monoclonal antibody. Although this drug did not meet the primary clinical endpoints, some significant associations were found with exploratory biomarkers.

METHOD: We analyzed rs-fMRI of participants with MCI due to AD and mild AD at screening and week 116 collected in a subgroup of the randomized, double-blind, pivotal, Phase III trials GRADUATE I (273 patients, 52% female, 50% placebo) and GRADUATE II (335 patients, 59% female, 57% placebo) (NCT03444870, NCT04374253). Using group Independent Components Analysis (GIFT, Calhoun et al., 2001), we extracted 25 resting states components in each clinical trial and grouped them into 7 networks (Sensory Motor, Cerebellar, Visual, SubCortical, Auditory, Default Mode and Cognitive Control). Using a linear model, we investigated changes in between- and within-networks brain connectivity at screening and week 116 in gantenerumab and placebo participants. The components-wise Pearson's correlation (Z-Fisher score) was used as the dependent variable, group (gantenerumab vs placebo), visit (screening vs week 116) and the interaction term group-by-visit as covariates of interest, while controlling for sex, age and scanner magnetic field strength (1.5T vs 3T). This analysis was exploratory in nature and no adjustment for multiple components-wise comparisons was applied.

RESULT: In both GRADUATE I and II, we found a significant group-by-visit effect (p < 0.05). Specifically, we found decreasing within- and between-networks functional connectivity in the placebo group at week 116 compared to screening. Conversely, the gantenerumab group reported stable or higher connectivity at week 116 compared to screening (Fig. 1-2).

CONCLUSION: These results suggest a potential relationship between amyloid removal and changes in brain functional connectivity. Due to the exploratory nature of this study further investigation is needed to confirm these findings.

PMID:39783456 | DOI:10.1002/alz.094926

Developing Topics

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 8:e094682. doi: 10.1002/alz.094682.

ABSTRACT

BACKGROUND: Mild Cognitive Impairment (MCI) serves as a precursor to Alzheimer's dementia (AD). Recent research underscores the relationship between mitochondrial dysfunction and amyloid beta accumulation, underscoring the prospect of targeting mitochondrial function for intervention. Consequently, our study aimed to explore the efficacy of transcranial photobiomodulation (tPBM), a novel non-invasive technique utilizing near-infrared light to activate mitochondrial cytochrome C oxidase receptors, thereby enhancing cellular energy in individuals with MCI.

METHODS: Fifteen MCI patients were randomly allocated to either active or sham groups (8 active, 7 sham), with both groups receiving indistinguishable active and sham tPBM devices. Over a span of 6 weeks, participants underwent daily home-based tPBM sessions. Pre- and post-treatment assessments included a comprehensive battery of tests, encompassing the Trail Making Test (TMT B & A), Mini-Mental State Examination (MMSE), Proton Magnetic Resonance Spectroscopy (H-MRS) of the posterior cingulate cortex, structural MRI, resting-state functional MRI (rsfMRI), and blood analyses.

RESULTS: In the active treatment group compared to the sham group, significant findings (p<0.05) emerged including: 1) faster executive functioning (reduced TMT B completion time), and a promising trend of enhanced MMSE and TMT B/A scores. 2) H-MRS analysis revealed a decreased ratio of N-acetyl aspartate to creatine (NAA/Cr), indicating improved neuronal health. 3) Structural MRI showed increased volume of the right thalamus. 4) Functional connectivity analysis using rs-fMRI data unveiled higher change in the default mode network (DMN) and limbic network, as well as between DMN and executive control network (ECN). 5) Blood tests showcased decreases in isoleucine, methionine, and sarcosine levels-markers linked to AD and amyloid plaque formation-while displaying increases in butyrate, L-carnitine, and L-arginine levels-markers indicative of improved mitochondrial function. Furthermore, a notable trend towards decreased levels of tau protein was observed.

CONCLUSIONS: Our preliminary findings suggest a potential therapeutic benefit of tPBM in MCI, possibly through the augmentation of mitochondrial function. However, extending the treatment duration may yield further improvements in cognition. Parameters such as NAA/Cr ratios via H-MRS, DMN functional connectivity via rs-fMRI, and blood metabolites may serve as objective indicators of response to tPBM treatment. Nevertheless, conclusive determinations require a larger sample size.

PMID:39783431 | DOI:10.1002/alz.094682

Developing Topics

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095630. doi: 10.1002/alz.095630.

ABSTRACT

BACKGROUND: The locus coeruleus (LC) is one of the earliest regions accumulating tau pathology in Alzheimer's Disease (AD). As the disease progresses, tau in the LC has been linked to increasing cortical tau and amyloid-beta (Aβ) pathologies and cognitive decline. Previous animal research suggested that novelty-like phasic LC activity protects against AD-related cognitive decline. In this work, we investigate whether in-vivo resting-state phasic LC activity is associated with AD pathology and cognitive decline in preclinical AD.

METHOD: Ninety-two participants (56 Female, mean age at baseline = 74.99±9.0 years) from the Harvard Aging Brain Study underwent longitudinal cognitive testing (mean follow-up = 5.37±1.88 years), PiB(Aβ)-PET, FTP(tau)-PET, and 3T resting-state BOLD-fMRI scans (TR/TE = 800/37 ms, voxel = 2 mm3) performed within 1.5 years of each other (mean time difference = 0.96±0.0 years; Table 1). Spontaneous phasic LC activity events were extracted directly from the LC BOLD-fMRI time-series using deconvolution and positively-constrained LASSO regression. The proportion of LC activity explained by the detected events was quantified using the R-squared coefficient of determination. Vertex-wise linear regression analyses adjusted for age, sex, and multiple comparisons (pcl<0.05) were used to detect significant associations between LC phasic activity and cortical tau. Longitudinal linear mixed-model analyses adjusted for age, sex, and years of education were used to evaluate the relationship between LC phasic activity and cognitive decline (composite, see Fig. 2 caption) at different levels of cortical Aβ.

RESULT: Representative spontaneous LC phasic events and their associated BOLD-fMRI signal fluctuations are illustrated in Fig. 1A-B, respectively. Lower resting-state phasic LC activity was associated with greater bilateral inferior-temporal tau deposition (Fig. 1C), also confirmed by a region of interest analysis (Fig. 1D; p = 0.03). No relationship between phasic LC activity and Aβ was observed. Furthermore, lower LC phasic activity was associated with steeper cognitive (Fig. 2; p = 0.02) decline, particularly at elevated Aβ levels.

CONCLUSION: This preliminary work demonstrates that lower levels of spontaneous phasic LC activity are related to elevated cortical tau pathology and steeper downstream AD-related cognitive decline. These results could inform the design of targeted interventions to support optimal LC phasic activity, promoting resilience. Further research is needed to elucidate these relationships further by utilizing longitudinal data on AD pathology and cognitive function across different subdomains.

PMID:39783408 | DOI:10.1002/alz.095630

Developing Topics

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095431. doi: 10.1002/alz.095431.

ABSTRACT

BACKGROUND: We investigated heterogeneities in clinical progression trajectories among cognitively impaired (CI) older adults who were positive for both beta-amyloid (Aβ) and neurodegeneration biomarkers of Alzheimer's disease (AD) using trajectory clustering analysis. We then compared clinical and neuroimaging variables across clusters with different clinical trajectories.

METHOD: CI older adults, consisting of individuals with mild cognitive impairment (MCI) or mild AD dementia were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE). All participants underwent comprehensive clinical assessment, and multi-modal neuroimaging including 11C-PiB PET, 18F-FDG PET, and MRI with resting-state functional MRI (fMRI). Among them, participants who were both amyloid positive (A+) and neurodegeneration positive (N+), including those with hypometabolism and cortical thinning in AD-vulnerable regions, as well as hippocampal atrophy, were included. A subset of participants underwent 18F-AV1451 PET to measure brain tau deposition. Group-based trajectory modeling (GBTM) using the Clinical Dementia Rating (CDR)-Sum of boxes (SOB) measured at baseline and longitudinal follow-up up to four years, was used to identify clusters among A+N+ CI participants.

RESULT: A total of 86 A+N+ CI individuals were included for the final analysis. A GBTM, based on longitudinal CDR-SOB, identified two clusters with different trajectories: Cluster A (N = 54 [62.8%]) with slow progression and Cluster B (N = 32 [37.2%]) with rapid progression (Figure 1). No significant differences among age, sex, educational years, clinical diagnosis, global CDR, and APOE e4 carrier status were observed between the two clusters at baseline. These two clusters did not differ regarding global tau deposition and Braak Stages in a subset of participants (N = 34). However, at baseline, network segregation measure for the whole cortex and sensory-motor network, and functional connectivity (FC) within the sensory-motor network, differed between the two clusters after adjusting for age, sex, and education.

CONCLUSION: Our study identified two clusters with heterogeneous clinical progression trajectories even among CI older adults who exhibited both Aβ and neurodegeneration biomarkers. Further studies are necessary to elucidate the relationship between resting-state FC measures and AD subtypes with different clinical trajectories.

PMID:39783304 | DOI:10.1002/alz.095431

Developing Topics

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095216. doi: 10.1002/alz.095216.

ABSTRACT

BACKGROUND: Isolated REM Sleep Behavior Disorder (iRBD) is a well-recognized prodromal state of an underlying α-synucleinopathy, occurring several years before an overt neurodegenerative disorder becomes fully manifest. iRBD has been related to poorer cognitive performance and higher frequency of mild cognitive impairment (MCI). The aim of this study was to explore in detail, with structural and functional MRI, frontal-executive dysfunction in iRBD patients and to evaluate its association with cognitive performance.

METHOD: Thirty-two iRBD patients (24 males; age, mean±SD = 67.9±7.1 years) and thirty age-matched healthy controls were recruited and underwent an extensive neuropsychological assessment and multiparametric MR acquisition. The MR protocol (3T) included T1-w volumetric (isotropic 1mm3), diffusion weighted imaging (b = 2000 s/mm2, 64 directions) and resting-state (TR = 0.735s, 10 minutes) acquisitions. Brain volumetry analysis was conducted using FreeSurfer. TBSS was applied to evaluate white matter microstructural alterations. Resting state networks were investigated with ICA. Correlations between MR parameters and neuropsychological variables were explored with Spearman's test.

RESULT: iRBD patients, when compared with healthy controls, showed worse performance on tests related to attentive-executive, memory, and visuospatial functions (i.e., cancellation test p = 0.041, similarities p = 0.015, 15-words recall p = 0.004, and simple drawing copy p = 0.007); they also showed volume reduction in left rostral anterior cingulate (p = 0.005). TBSS highlighted increased anterior corpus callosum and forceps minor Radial Diffusivity in iRBD patients (p <0.05). Significant correlations were found between this alteration and executive dysfunctions (i.e. Stroop test, r = 0.46, p = 0.009). Moreover, fMRI data showed 'Executive control' network alteration in iRBD patients within cortical (i.e. superior and middle frontal gyrus, opercular cortex, paracingulate and precentral gyrus) and subcortical structures (i.e. putamen and caudate); these data correlated with worse performance in executive-attentive tests (i.e., cancellation time, r = -0.45, p = 0.018 and frontal assessment battery, r = 0.44, p = 0.023).

CONCLUSION: This study showed that structural and functional frontal-executive alterations in iRBD patients are associated with attentive-executive functioning, findings that are similar to those observed in some synucleinopathies. Further studies with bigger samples and follow-ups are needed to confirm these results, and to monitor the trajectory of these alterations longitudinally. Acknowledgement: This study was supported by the Italian Ministry of Health (#GR-2019-12369242).

PMID:39783267 | DOI:10.1002/alz.095216

Alzheimer's Imaging Consortium

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 9:e093652. doi: 10.1002/alz.093652.

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:39783244 | DOI:10.1002/alz.093652