Most recent paper

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

Alzheimer's Imaging Consortium

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 9:e093612. doi: 10.1002/alz.093612.

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:39783210 | DOI:10.1002/alz.093612

Developing Topics

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095766. doi: 10.1002/alz.095766.

ABSTRACT

BACKGROUND: Neural flexibility (NF) during tasks was associated with cognitive aging, while that during rest was not associated with aging and cognition in a healthy aging population. However, NF has not been studied in AD. We aim to evaluate whether AD is associated with alterations in NF and probe its predictive utility for AD conversion.

METHOD: The study included 862 older adults with valid resting-state fMRI data: 461 who are cognitively normal (CN, 53.5%), 294 with Mild cognitive impairment (MCI, 34.1%), and 107 with Alzheimer's Disease (AD, 12.4%) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The MRI images were processed using fMRIPrep, and the mean time series of each node was extracted according to the Power Atlas parcellation scheme. We performed dynamic community detection based on generalized Louvain methods. We defined the NF of a node as the number of times that a node changed its community assignment across the sliding windows, normalized by the total number of possible changes and computed global NF (GNF) and network-level NF. We performed linear mixed models on NF to explore the effect of AD group indicators on NF controlling for the age at scan, gender, education level, and the random intercept of site. We then evaluated the dementia transition of neural flexibility using survival analysis. In the non-demented participants at baseline, we performed Cox-proportional hazard regression analysis with each NF.

RESULTS: NF is significantly higher in AD group than the CN group on global, CON, MRN, SMN-H, SMN-M, VAN, and VIS networks (Figure 1); neural flexibility is significantly higher in the MCI group than the CN group in the VIS network (Figure 1). Among n = 670 non-demented participants at baseline, n = 53 (8.6%) participants converted to dementia during the follow-ups. Higher neural flexibility in VIS was positively associated with AD transition (HR = 1.323, 95%CI 1.002 to 1.747, p = 0.049, per 1 standard deviation in NF, Figure 2), controlling for age, gender, and education.

CONCLUSION: We found that NF during resting was higher in AD patients and predicted dementia transition. Thus, NF can be a valuable biomarker of AD, and more validation and mechanistic studies need to be performed.

PMID:39783197 | DOI:10.1002/alz.095766

Alzheimer's Imaging Consortium

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 9:e093781. doi: 10.1002/alz.093781.

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; Fig. 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; Fig. 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:39783120 | DOI:10.1002/alz.093781

Alzheimer's Imaging Consortium

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 9:e093813. doi: 10.1002/alz.093813.

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 Aß, p-tau, resting-state fMRI and longitudinal cognitive assessment (average follow-up time = 3.35 years, SD = 0.53). CSF Aß42 and Aß40 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 Aß42/40 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 (Fig. 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 Aß42/40 and longitudinal PACC (Fig. 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 Aß42/40 on longitudinal memory performance (Fig.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:39783110 | DOI:10.1002/alz.093813

Dementia Care Research and Psychosocial Factors

Thu, 01/09/2025 - 19:00

Alzheimers Dement. 2024 Dec;20 Suppl 4:e093289. doi: 10.1002/alz.093289.

ABSTRACT

BACKGROUND: Repetitive transcranial magnetic stimulation enhances cognition in people with mild cognitive impairment (MCI). Whereas conventional treatment requires daily sessions for 4-6 weeks, accelerated intermittent theta burst stimulation (iTBS) shortens the treatment course to just 3 days, substantially improving feasibility of use in people with MCI. We conducted a Phase I safety and feasibility trial of iTBS in MCI, finding preliminary evidence of cognitive improvement. Here, we explore the neural mechanism of this effect by evaluating iTBS-related changes in functional connectivity in relation to the observed cognitive change.

METHOD: Twenty-two patients with amnestic MCI received iTBS to left dorsolateral prefrontal cortex (l-dlPFC) over 3 treatment days (with 8 stimulation sessions of 600 pulses per day) within 1 week. Nineteen had complete MRI and cognitive testing data. The primary cognitive outcome was the fluid cognition composite score from the NIH Toolbox Cognition Battery. We computed functional connectivity from resting-state fMRI and calculated participation coefficient for three regions of interest. Lower participation coefficient values indicate that a region is more selectively connected to its own network and higher values indicate that it is more widely connected across networks (i.e., a "hub"). We calculated change in participation coefficient from pre- to post-treatment for two regions belonging to the frontoparietal network (the l-dlPFC iTBS target and the contralateral right dlPFC) and a negative control (primary visual; V1).

RESULT: There was a significant, large effect-size (d = 0.98) improvement in fluid cognition from pre- to post-iTBS treatment. Improvements in cognition were significantly associated with increased participation coefficient of l-dlPFC (r = .52, p = .022), with a marginal effect in r-dlPFC (r = .41, p = .084) and a near zero effect in the negative control V1 (r = .03, p = .898).

CONCLUSION: This preliminary investigation suggests that iTBS-related cognitive improvement in MCI may be attributable to increased connectivity of the stimulated frontoparietal network. Specifically, a larger increase in "hubness" (i.e., connectivity across multiple networks) of the l-dlPFC target region is associated with greater cognitive gains. However, as these analyses are based on a limited number of regions and small sample, future studies are needed to further evaluate the neural mechanisms of iTBS in MCI.

PMID:39782041 | DOI:10.1002/alz.093289

Reconstruction and application of multilayer brain network for juvenile myoclonic epilepsy based on link prediction

Thu, 01/09/2025 - 19:00

Cogn Neurodyn. 2025 Dec;19(1):7. doi: 10.1007/s11571-024-10191-0. Epub 2025 Jan 6.

ABSTRACT

Juvenile myoclonic epilepsy (JME) exhibits abnormal functional connectivity of brain networks at multiple frequencies. We used the multilayer network model to address the heterogeneous features at different frequencies and assess the mechanisms of functional integration and segregation of brain networks in JME patients. To address the possibility of false edges or missing edges during network construction, we combined multilayer networks with link prediction techniques. Resting-state functional magnetic resonance imaging (rs-fMRI) data were procured from 40 JME patients and 40 healthy controls. The Multilayer Network framework is utilized to integrate information from different frequency bands and to fuse similarity metrics for link prediction. Finally, calculate the entropy of the multiplex degree and multilayer clustering coefficient of the reconfigured multilayer frequency network. The results showed that the multilayer brain network of JME patients had significantly reduced ability to integrate and separate information and significantly correlated with severity of JME symptoms. This difference was particularly evident in default mode network (DMN), motor and somatosensory network (SMN), and auditory network (AN). In addition, significant differences were found in the precuneus, suboccipital gyrus, middle temporal gyrus, thalamus, and insula. Results suggest that JME patients have abnormal brain function and reduced cross-frequency interactions. This may be due to changes in the distribution of connections within and between the DMN, SMN, and AN in multiple frequency bands, resulting in unstable connectivity patterns. The generation of these changes is related to the pathological mechanisms of JME and may exacerbate cognitive and behavioral problems in patients.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11571-024-10191-0.

PMID:39780908 | PMC:PMC11703786 | DOI:10.1007/s11571-024-10191-0

Connectome-Based Predictive Modeling of Trait Mindfulness

Thu, 01/09/2025 - 19:00

Hum Brain Mapp. 2025 Jan;46(1):e70123. doi: 10.1002/hbm.70123.

ABSTRACT

Trait mindfulness refers to one's disposition or tendency to pay attention to their experiences in the present moment, in a non-judgmental and accepting way. Trait mindfulness has been robustly associated with positive mental health outcomes, but its neural underpinnings are poorly understood. Prior resting-state fMRI studies have associated trait mindfulness with within- and between-network connectivity of the default-mode (DMN), fronto-parietal (FPN), and salience networks. However, it is unclear how generalizable the findings are, how they relate to different components of trait mindfulness, and how other networks and brain areas may be involved. To address these gaps, we conducted the largest resting-state fMRI study of trait mindfulness to-date, consisting of a pre-registered connectome-based predictive modeling analysis in 367 meditation-naïve adults across three samples collected at different sites. In the model-training dataset, we did not find connections that predicted overall trait mindfulness, but we identified neural models of two mindfulness subscales, Acting with Awareness and Non-judging. Models included both positive networks (sets of pairwise connections that positively predicted mindfulness with increasing connectivity) and negative networks, which showed the inverse relationship. The Acting with Awareness and Non-judging positive network models showed distinct network representations involving FPN and DMN, respectively. The negative network models, which overlapped significantly across subscales, involved connections across the whole brain with prominent involvement of somatomotor, visual and DMN networks. Only the negative networks generalized to predict subscale scores out-of-sample, and not across both test datasets. Predictions from both models were also negatively correlated with predictions from a well-established mind-wandering connectome model. We present preliminary neural evidence for a generalizable connectivity models of trait mindfulness based on specific affective and cognitive facets. However, the incomplete generalization of the models across all sites and scanners, limited stability of the models, as well as the substantial overlap between the models, underscores the difficulty of finding robust brain markers of mindfulness facets.

PMID:39780500 | DOI:10.1002/hbm.70123

Intermittent Fasting Enhances Motor Coordination Through Myelin Preservation in Aged Mice

Thu, 01/09/2025 - 19:00

Aging Cell. 2025 Jan 8:e14476. doi: 10.1111/acel.14476. Online ahead of print.

ABSTRACT

Integrating dietary interventions have been extensively studied for their health benefits, such as Alzheimer's disease, Huntington's disease, and aging. However, it is necessary to fully understand the mechanisms of long-term effects and practical applications of these dietary interventions for health. A 10-week intermittent fasting (IMF) regimen was implemented on the aging animals in the current study. The variations of cerebral functions were analyzed employing a comprehensive experimental design that includes behavioral tests, neuroimaging, and ultrastructural analysis, such as resting-state functional MRI (rsfMRI), EEG/EMG recordings, transmission electron microscopy, and immunohistochemistry. Over a 10-week regimen, IMF significantly improved locomotor activity, motor coordination, and muscle strength compared to controls (p < 0.01). Resting-state fMRI (rsfMRI) demonstrated that IMF modulates brain-wide functional connectivity, enhancing communication between key brain regions. Advanced imaging techniques revealed increased expression of myelin-related proteins, including myelin basic protein (MBP), and myelin-associated glycoprotein (MAG), indicating enhanced myelin integrity and repair, particularly in axons with diameters < 400 nm (p < 0.01). These findings suggest that IMF may mitigate age-related declines by promoting better neuronal signaling. This study highlights the potential function of IMF as a non-pharmacological intervention to promote brain health and mitigate cognitive decline in aging populations.

PMID:39780365 | DOI:10.1111/acel.14476

Alterations in cerebral perfusion and corresponding brain functional networks in systemic lupus erythematosus with cognitive impairment

Wed, 01/08/2025 - 19:00

Sci Rep. 2025 Jan 8;15(1):1310. doi: 10.1038/s41598-025-85648-1.

ABSTRACT

Cognitive impairment (CI) frequently occurs in patients with systemic lupus erythematosus (SLE) and may result from neuroinflammation processes and neurovascular changes in the brain. The cerebral hemodynamics underlying SLE with CI (SLE-CI) remain unclear. 97 patients with SLE and 51 heathy controls (HCs) matched for age and gender underwent MRI. The CI status of patients was measured using the MoCA, and we classify those with a score of 28 or above as the SLE cognitive normal group (SLE-NC). 3D T1-weighted, ASL and resting-state functional (rs-fMRI) sequences were obtained. Seed-based functional connectivity (FC) was calculated using the cerebral blood flow (CBF) results. Compared with SLE-NC, patients with SLE-CI had higher CBF in the left hippocampus, thalamus, and cerebellum crus II and lower CBF in the left frontal lobe. Secondary analyses revealed that compared with patients with SLE-NC, patients with SLE-CI had increased FC of the left insula gyrus when the left cerebellum crus II was set as the seed region and decreased FC in the homolateral para-hippocampus when the left hippocampus was set as the seed region. These structural, functional, and network changes may serve as potential biomarkers for cognitive impairment in SLE-CI patients.

PMID:39779789 | DOI:10.1038/s41598-025-85648-1

Resting State Functional Connectivity of the Default Mode Network During Opioid Use and Cessation in Treatment-Seeking Persons

Wed, 01/08/2025 - 19:00

Eur J Neurosci. 2025 Jan;61(1):e16656. doi: 10.1111/ejn.16656.

ABSTRACT

Resting-state functional connectivity analyses have been used to examine synchrony in neural networks in substance use disorders (SUDs), with the default mode network (DMN) one of the most studied. Prior research has generally found less DMN synchrony during use and greater synchrony during cessation, although little research has utilized this method with opioid use. This study examined resting brain activity in treatment-seeking persons who use opioids at two points-when using opioids and when opioid-free-to determine whether the DMN exhibits different levels of connectivity during opioid use and cessation and whether differences in connectivity predict subsequent relapse. The sample included 11 participants who met DSM-5 criteria for opioid use disorder and initiated buprenorphine treatment following fMRI scans that were approximately 3 days apart. Results showed greater functional connectivity in the DMN and the rIFG of the salience network (SN) when participants were abstaining than when actively using opioids. These changes in connectivity predicted 76.2% of the variance in withdrawal symptom severity, with the DMN nodes accounting for an additional 30.9%. Findings warrant further longitudinal exploration of the role of DMN connectivity and its interactions with other networks in relation to abstinence and withdrawal status and examination of its utility as a prognostic marker of cessation or relapse.

PMID:39779490 | DOI:10.1111/ejn.16656