Total Synthesis of a PSGL-1 Glycopeptide Analogue for Targeted Inhibition of P-Selectin.

The high affinity interaction between P-selectin glycoprotein ligand-1 (PSGL-1) and P-selectin is mediated by a multimotif glycosulfopeptide (GSP) recognition domain consisting of clustered tyrosine sulfates and a Core 2 O-glycan terminated with sialyl LewisX (C2-O-sLeX). These distinct GSP motifs are much more common than previously appreciated within a wide variety of functionally important domains involved in protein-protein interactions. However, despite the potential of GSPs to serve as tools for fundamental studies and prospects for drug discovery, their utility has been limited by the absence of chemical schemes for synthesis on scale. Herein, we report the total synthesis of GSnP-6, an analogue of the N-terminal domain of PSGL-1, and potent inhibitor of P-selectin. An efficient, scalable, hydrogenolysis-free synthesis of C2-O-sLeX-Thr-COOH was identified by both convergent and orthogonal one-pot assembly, which afforded this crucial building block, ready for direct use in solid phase peptide synthesis (SPPS). C2-O-sLeX-Thr-COOH was synthesized in 10 steps with an overall yield of 23% from the 4-O,5-N oxazolidinone thiosialoside donor. This synthesis represents an 80-fold improvement in reaction yield as compared to prior reports, achieving the first gram scale synthesis of SPPS ready C2-O-sLeX-Thr-COOH and enabling the scalable synthesis of GSnP-6 for preclinical evaluation. Significantly, we established that GSnP-6 displays dose-dependent inhibition of venous thrombosis in vivo and inhibits vaso-occlusive events in a human sickle cell disease equivalent microvasculature-on-a-chip system. The insights gained in formulating this design strategy can be broadly applied to the synthesis of a wide variety of biologically important oligosaccharides and O-glycan bearing glycopeptides.

Cerebrospinal fluid amyloid-ß and cerebral microbleed are associated with distinct neuropsychiatric sub-syndromes in cognitively impaired patients.

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent in cognitively impaired individuals including Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). Whereas several studies have reported the associations between NPS with AD pathologic biomarkers and cerebral small vessel disease (SVD), but it remains unknown whether AD pathology and SVD contribute to different sub-syndromes independently or aggravate same symptoms synergistically. METHOD: We included 445 cognitively impaired individuals (including 316 MCI and 129 AD) with neuropsychiatric, cerebrospinal fluid (CSF) biomarkers (Aß42, p-tau, and t-tau) and multi-model MRI data. Psychiatric symptoms were accessed by using the Neuropsychiatric Inventory (NPI). Visual assessment of SVD (white matter hyperintensity, microbleed, perivascular space, lacune) on MRI images was performed by experienced radiologist. Linear regression analyses were conducted to test the association between neuropsychiatric symptoms with AD pathology and CSVD burden after adjustment for age, sex, education, apolipoprotein E (APOE) ε4 carrier status, and clinical diagnosis. RESULTS: The NPI total scores were related to microbleed (estimate 2.424; 95% CI [0.749, 4.099]; P =0.005). Considering the sub-syndromes, the hyperactivity was associated with microbleed (estimate 0.925; 95% CI [0.115, 1.735]; P =0.025), whereas the affective symptoms were correlated to CSF level of Aß42 (estimate -0.006; 95% CI [-0.011, -0.002]; P =0.005). Furthermore, we found the apathy sub-syndrome was associated with CSF t-tau/Aß42 (estimate 0.636; 95% CI [0.078, 1.194]; P =0.041) and microbleed (estimate 0.693; 95% CI [0.046, 1.340]; P =0.036). In addition, we found a significant interactive effect between CSF t-tau/Aß42 and microbleed (estimate 0.993; 95% CI [0.360, 1.626]; P =0.019) on severity of apathy sub-syndrome. CONCLUSION: Our study showed that CSF Aß42 was associated with affective symptoms, but microbleed was correlated with hyperactivity and apathy, suggesting the effect of AD pathology and SVD on different neuropsychiatric sub-syndromes.

Alteration of functional connectivity network in population of objectively-defined subtle cognitive decline.

The objectively-defined subtle cognitive decline individuals had higher progression rates of cognitive decline and pathological deposition than healthy elderly, indicating a higher risk of progressing to Alzheimer's disease. However, little is known about the brain functional alterations during this stage. Thus, we aimed to investigate the functional network patterns in objectively-defined subtle cognitive decline cohort. Forty-two cognitive normal, 29 objectively-defined subtle cognitive decline and 55 mild cognitive impairment subjects were included based on neuropsychological measures from the Alzheimer's disease Neuroimaging Initiative dataset. Thirty cognitive normal, 22 objectively-defined subtle cognitive declines and 48 mild cognitive impairment had longitudinal MRI data. The degree centrality and eigenvector centrality for each participant were calculated by using resting-state functional MRI. For cross-sectional data, analysis of covariance was performed to detect between-group differences in degree centrality and eigenvector centrality after controlling age, sex and education. For longitudinal data, repeated measurement analysis of covariance was used for comparing the alterations during follow-up period among three groups. In order to classify the clinical significance, we correlated degree centrality and eigenvector centrality values to Alzheimer's disease biomarkers and cognitive function. The results of analysis of covariance showed significant between-group differences in eigenvector centrality and degree centrality in left superior temporal gyrus and left precuneus, respectively. Across groups, the eigenvector centrality value of left superior temporal gyrus was positively related to recognition scores in auditory verbal learning test, whereas the degree centrality value of left precuneus was positively associated with mini-mental state examination total score. For longitudinal data, the results of repeated measurement analysis of covariance indicated objectively-defined subtle cognitive decline group had the highest declined rate of both eigenvector centrality and degree centrality values than other groups. Our study showed an increased brain functional connectivity in objectively-defined subtle cognitive decline individuals at both local and global level, which were associated with Alzheimer's disease pathology and neuropsychological assessment. Moreover, we also observed a faster declined rate of functional network matrix in objectively-defined subtle cognitive decline individuals during the follow-ups.

Small vessel disease and cognitive reserve oppositely modulate global network redundancy and cognitive function: A study in middle-to-old aged community participants.

Cerebral small vessel disease (SVD) can disrupt the global brain network and lead to cognitive impairment. Conversely, cognitive reserve (CR) can improve one's cognitive ability to handle damaging effects like SVD, partly by optimizing the brain network's organization. Understanding how SVD and CR collectively influence brain networks could be instrumental in preventing cognitive impairment. Recently, brain redundancy has emerged as a critical network protective metric, providing a nuanced perspective of changes in network organization. However, it remains unclear how SVD and CR affect global redundancy and subsequently cognitive function. Here, we included 121 community-dwelling participants who underwent neuropsychological assessments and a multimodal MRI examination. We visually examined common SVD imaging markers and assessed lifespan CR using the Cognitive Reserve Index Questionnaire. We quantified the global redundancy index (RI) based on the dynamic functional connectome. We then conducted multiple linear regressions to explore the specific cognitive domains related to RI and the associations of RI with SVD and CR. We also conducted mediation analyses to explore whether RI mediated the relationships between SVD, CR, and cognition. We found negative correlations of RI with the presence of microbleeds (MBs) and the SVD total score, and a positive correlation of RI with leisure activity-related CR (CRI-leisure). RI was positively correlated with memory and fully mediated the relationships between the MBs, CRI-leisure, and memory. Our study highlights the potential benefits of promoting leisure activities and keeping brain redundancy for memory preservation in older adults, especially those with SVD.

Association Between Small Vessel Disease and Financial Capacity: A Study Based on Cognitively Normal Older Adults.

Background: Financial capacity is vital for the elderly, who possess a substantial share of global wealth but are vulnerable to financial fraud. Objective: We explored the link between small vessel disease (SVD) and financial capacity in cognitively unimpaired (CU) older adults via both cross-sectional and longitudinal analyses. Methods: 414 CU participants underwent MRI and completed the Financial Capacity Instrument-Short Form (FCI-SF). Subsequent longitudinal FCI-SF data were obtained from 104, 240, and 141 participants at one, two, and four years, respectively. SVD imaging markers, encompassing white matter hyperintensities (WMH), cerebral microbleeds (CMB), and lacune were evaluated. We used linear regression analyses to cross-sectionally explore the association between FCI-SF and SVD severity, and linear mixed models to assess how baseline SVD severity impacted longitudinal FCI-SF change. The false discovery rate method was used to adjust multiple comparisons. Results: Cross-sectional analysis revealed a significant association between baseline WMH and Bank Statement (BANK, ß=-0.194), as well as between lacune number and Financial Conceptual Knowledge (FC, ß= -0.171). These associations were stronger in APOE ɛ4 carriers, with ß= -0.282 for WMH and BANK, and ß= -0.366 for lacune number and FC. Longitudinally, higher baseline SVD total score was associated with severe FCI-SF total score decrease (ß= -0.335). Additionally, baseline WMH burden predicted future decreases in Single Checkbook/Register Task (SNG, ß= -0.137) and FC (ß= -0.052). Notably, the association between baseline WMH and SNG changes was amplified in APOE ɛ4 carriers (ß= -0.187). Conclusions: Severe SVD was associated with worse FCI-SF and could predict the decline of financial capacity in CU older adults.

Effect of cerebral small vessel disease on the integrity of cholinergic system in mild cognitive impairment patients: a longitudinal study.

We aimed to investigate the effect of cerebral small vessel disease (SVD) on cholinergic system integrity in mild cognitive impairment (MCI) patients. Nucleus basalis of Meynert (NBM) volume and cholinergic pathways integrity was evaluated at baseline, 1-, 2-, and 4-year follow-ups in 40 cognitively unimpaired (CU) participants, 29 MCI patients without SVD, and 23 MCI patients with SVD. We compared cholinergic markers among three groups and examined their associations with SVD burden in MCI patients. We used linear mixed models to assess longitudinal changes in cholinergic markers over time among groups. Mediation analysis was employed to investigate the mediating role of cholinergic system degeneration between SVD and cognitive impairment. Increased mean diffusivity (MD) in medial and lateral pathways was observed in MCI patients with SVD compared to those without SVD and CU participants. Both MCI groups showed decreased NBM volume compared to CU participants, while there was no significant difference between the two MCI groups. Longitudinally, compared to CU participants, MCI patients with SVD displayed a more rapid change in MD in both pathways, but not in NBM volume. Furthermore, SVD burden was associated with cholinergic pathway disruption and its faster rate of change in MCI patients. However, mediation analyses showed that cholinergic pathways did not mediate significant indirect effects of SVD burden on cognitive impairment. Our findings suggest that SVD could accelerate the degeneration of cholinergic pathways in MCI patients. However, they do not provide evidence to support that SVD could contribute to cognitive impairment through cholinergic system injury.

The relationship between amyloid pathology, cerebral small vessel disease, glymphatic dysfunction, and cognition: a study based on Alzheimer's disease continuum participants.

BACKGROUND: Glymphatic dysfunction is a crucial pathway for dementia. Alzheimer's disease (AD) pathologies co-existing with cerebral small vessel disease (CSVD) is the most common pathogenesis for dementia. We hypothesize that AD pathologies and CSVD could be associated with glymphatic dysfunction, contributing to cognitive impairment. METHOD: Participants completed with amyloid PET, diffusion tensor imaging (DTI), and T2 fluid-attenuated inversion-recovery (FLAIR) sequences were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI). White matter hyperintensities (WMH), the most common CSVD marker, was evaluated from T2FLAIR images and represented the burden of CSVD. Amyloid PET was used to assess Aß aggregation in the brain. We used diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, the burden of enlarged perivascular spaces (PVS), and choroid plexus volume to reflect glymphatic function. The relationships between WMH burden/Aß aggregation and these glymphatic markers as well as the correlations between glymphatic markers and cognitive function were investigated. Furthermore, we conducted mediation analyses to explore the potential mediating effects of glymphatic markers in the relationship between WMH burden/Aß aggregation and cognition. RESULTS: One hundred and thirty-three participants along the AD continuum were included, consisting of 40 CN - , 48 CN + , 26 MCI + , and 19 AD + participants. Our findings revealed that there were negative associations between whole-brain Aß aggregation (r = - 0.249, p = 0.022) and WMH burden (r = - 0.458, p < 0.001) with DTI-ALPS. Additionally, Aß aggregation (r = 0.223, p = 0.041) and WMH burden (r = 0.294, p = 0.006) were both positively associated with choroid plexus volume. However, we did not observe significant correlations with PVS enlargement severity. DTI-ALPS was positively associated with memory (r = 0.470, FDR-p < 0.001), executive function (r = 0.358, FDR-p = 0.001), visual-spatial (r = 0.223, FDR-p < 0.040), and language (r = 0.419, FDR-p < 0.001). Conversely, choroid plexus volume showed negative correlations with memory (r = - 0.315, FDR-p = 0.007), executive function (r = - 0.321, FDR-p = 0.007), visual-spatial (r = - 0.233, FDR-p = 0.031), and language (r = - 0.261, FDR-p = 0.021). There were no significant correlations between PVS enlargement severity and cognitive performance. In the mediation analysis, we found that DTI-ALPS acted as a mediator in the relationship between WMH burden/Aß accumulation and memory and language performances. CONCLUSION: Our study provided evidence that both AD pathology (Aß) and CSVD were associated with glymphatic dysfunction, which is further related to cognitive impairment. These results may provide a theoretical basis for new targets for treating AD.

An Investigation of Cerebral Vascular Functional Properties in Middle-to-Old Age Community People With High Vascular Risk Profiles.

BACKGROUND: Vascular degeneration is an important cause of brain damage in aging. Assessing the functional properties of the cerebral vascular system may aid early diagnosis and prevention. PURPOSE: To investigate the relationships between potential vascular functional markers and vascular risks, brain parenchymal damage, and cognition. STUDY TYPE: Retrospective. SUBJECTS: Two hundred two general community subjects (42-80 years, males/females: 127/75). FIELD STRENGTH/SEQUENCE: 3 T, spin echo T1W/T2W/FLAIR, resting-state functional MRI with an echo-planar sequence (rsfMRI), pseudo-continuous arterial spin labeling (pCASL) with a three-dimensional gradient-spin echo sequence. ASSESSMENT: Cerebral blood flow (CBF) in gray matter calculated using pCASL, blood transit times calculated using rsfMRI, and the SD of internal carotid arteries signal (ICAstd ) calculated using rsfMRI; visual assessment for lacunes; quantification of white matter hyperintensity volume; permutation test for quality control; collection of demographic and clinical data, Montreal Cognitive Assessment, Mini-Mental State Examination. STATISTICAL TESTS: Kolmogorov-Smirnov test; Spearman rank correlation analysis; Multivariable linear regression analysis controlling for covariates; The level of statistical significance was set at P < 0.05. RESULTS: Age was negatively associated with ICAstd (ß = -0.180). Diabetes was associated with longer blood transit time from large arteries to capillary bed (ß = 0.185, adjusted for age, sex, and intracranial volume). Larger ICAstd was associated with less presence of lacunes (odds ratio: 0.418, adjusted for age and sex). Higher gray matter CBF (ß = 0.154) and larger ICAstd (ß = 0.136) were associated with better MoCA scores (adjusted for age, sex, and education). DATA CONCLUSION: Prolonged blood transit time, decreased ICAstd , and diminished CBF were associated with vascular dysfunction and cognitive impairment. They may serve as vascular functional markers in future studies. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Higher intracranial arterial pulsatility is associated with presumed imaging markers of the glymphatic system: An explorative study.

BACKGROUND: Arterial pulsation has been suggested as a key driver of paravascular cerebrospinal fluid flow, which is the foundation of glymphatic clearance. However, whether intracranial arterial pulsatility is associated with glymphatic markers in humans has not yet been studied. METHODS: Seventy-three community participants were enrolled in the study. 4D phase-contrast magnetic resonance imaging (MRI) was used to quantify the hemodynamic parameters including flow pulsatility index (PIflow) and area pulsatility index (PIarea) from 13 major intracerebral arterial segments. Three presumed neuroimaging markers of the glymphatic system were measured: including dilation of perivascular space (PVS), diffusivity along the perivascular space (ALPS), and volume fraction of free water (FW) in white matter. We explored the relationships between PIarea, PIflow, and the presumed glymphatic markers, controlling for related covariates. RESULTS: PIflow in the internal carotid artery (ICA) C2 segment (OR, 1.05; 95 % CI, 1.01-1.10, per 0.01 increase in PI) and C4 segment (OR, 1.05; 95 % CI, 1.01-1.09) was positively associated with the dilation of basal ganglia PVS, and PIflow in the ICA C4 segment (OR, 1.06, 95 % CI, 1.02-1.10) was correlated with the dilation of PVS in the white matter. ALPS was associated with PIflow in the basilar artery (ß, -0.273, p, 0.046) and PIarea in the ICA C2 (ß, -0.239, p, 0.041) and C7 segments (ß, -0.238, p, 0.037). CONCLUSIONS: Intracranial arterial pulsatility was associated with presumed neuroimaging markers of the glymphatic system, but the results were not consistent across different markers. Further studies are warranted to confirm these findings.

Identifying psychosis subtypes use individualized covariance structural differential networks and multi-site clustering.

BACKGROUND: Similarities among schizophrenia (SZ), schizoaffective disorder (SAD) and bipolar disorder (BP) including clinical phenotypes, brain alterations and risk genes, make it challenging to perform reliable separation among them. However, previous subtype identification that transcend traditional diagnostic boundaries were based on group-level neuroimaging features, ignoring individual-level inferences. METHODS: 455 psychoses (178 SZs, 134 SADs and 143 BPs), their first-degree relatives (N = 453) and healthy controls (HCs, N = 220) were collected from Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP I) consortium. Individualized covariance structural differential networks (ICSDNs) were constructed for each patient and multi-site clustering was used to identify psychosis subtypes. Group differences between subtypes in clinical phenotypes and voxel-wise fractional amplitude of low frequency fluctuation (fALFF) were calculated, as well as between the corresponding relatives. RESULTS: Two psychosis subtypes were identified with increased whole brain structural covariance, with decreased connectivity between amygdala-hippocampus and temporal-occipital cortex in subtype I (S-I) compared to subtype II (S-II), which was replicated under different clustering methods, number of edges and across datasets (B-SNIP II) and different brain atlases. S-I had higher emotional-related symptoms than S-II and showed significant fALFF decrease in temporal and occipital cortex, while S-II was more similar to HC. This pattern was consistently validated on relatives of S-I and S-II in both fALFF and clinical symptoms. CONCLUSIONS: These findings reconcile categorical and dimensional perspectives of psychosis neurobiological heterogeneity, indicating that relatives of S-I might have greater predisposition in developing psychosis, while relatives of S-II are more likely to be healthy. This study contributes to the development of neuroimaging informed diagnostic classifications within psychosis spectrum.

Identification of FXYD6 as the novel biomarker for glioma based on differential expression and DNA methylation.

OBJECTIVE: As a single-transmembrane protein of the FXYD family, FXYD6 plays different roles under physiological and pathological status, especially in the nervous system. This study aims to identify FXYD6 as a biomarker for glioma, by analyzing its expression and methylation patterns. METHODS: Using TCGA and GTEx datasets, we analyzed FXYD6 expression in various tissues, confirming its levels in normal brain and different glioma grades via immunoblotting and immunostaining. FXYD6 biological functions were explored through enrichment analysis, and tumor immune infiltration was assessed using ESTIMATE and TIMER algorithms. Pearson correlation analysis probed FXYD6 associations with biological function-related genes. A glioma detection model was developed using FXYD6 methylation data from TCGA and GEO. Consistently, a FXYD6 methylation-based prognostic model was constructed for glioma via LASSO Cox regression. RESULTS: FXYD6 was observed to be downregulated in GBM and implicated in a range of cellular functions, including synapse formation, cell junctions, immune checkpoint, ferroptosis, EMT, and pyroptosis. Hypermethylation of specific FXYD6 CpG sites in gliomas was identified, which could be used to build a diagnostic model. Additionally, FXYD6 methylation-based prognostic model could serve as an independent factor as well. CONCLUSIONS: FXYD6 is a promising biomarker for the diagnosis and prognosis of glioma, with its methylation-based prognostic model serving as an independent factor. This highlights its potential in clinical application for glioma management.

Gray matter structural covariance networks patterns associated with autopsy-confirmed LATE-NC compared to Alzheimer's disease pathology.

BACKGROUND: Cases with the limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC), Alzheimer's disease (AD), and mixed AD+TDP-43 pathology (AD+LATE-NC) share similar symptoms, which makes it a challenge for accurate diagnosis. Exploring the patterns of gray matter structural covariance networks (SCNs) in these three types may help to clarify the underlying mechanism and provide a basis for clinical interventions. METHODS: We included ante-mortem MRI data of 10 LATE-NC, 39  AD, and 25  AD+LATE-NC from the ADNI autopsy sample. We used four regions of interest (left posterior cingulate cortex, right entorhinal cortex, frontoinsular and dorsolateral prefrontal cortex) to anchor the default mode network (DMN), salience network (SN), and executive control network (ECN). Finally, we assessed the SCN alternations using a multi-regression model-based linear-interaction analysis. RESULTS: Cases with autopsy-confirmed LATE-NC and AD showed increased structural associations involving DMN, ECN, and SN. Cases with AD+LATE-NC showed increased structural association within DMN while decreased structural association between DMN and ECN. The volume of peak clusters showed significant associations with cognition and AD pathology. CONCLUSIONS: This study showed different SCN patterns in the cases with LATE-NC, AD, and AD+LATE-NC, and indicated the network disconnection mechanism underlying these three neuropathological progressions. Further, SCN may serve as an effective biomarker to distinguish between different types of dementia.

Degeneration of cholinergic white matter pathways and nucleus basalis of Meynert in individuals with objective subtle cognitive impairment.

We evaluated alterations in the nucleus basalis of Meynert (NBM) volume and integrity of cholinergic white matter pathways in objective subtle cognitive impairment (Obj-SCI) individuals. NBM segmentation and cholinergic pathways tracking were conducted at baseline, 12-, 24-, and 48-month follow-ups in 41 Obj-SCI individuals and 61 healthy controls (HC). The baseline and 4-year rate of change in NBM volume and cholinergic pathways mean diffusivity were compared. Associations between cholinergic index changes and pathological processes and cognitive performance were evaluated. After controlling for age, sex, APOE genotype, and total intracranial volume, Obj-SCI individuals exhibited reduced NBM volume and increased medial pathway mean diffusivity compared to HC at baseline. Furthermore, amyloid-positive Obj-SCI individuals exhibited a steeper longitudinal decline in NBM volume than HC. Additionally, decreases in NBM volume and cholinergic pathways integrity were associated with amyloid and vascular pathologies and cognitive decline. Overall, degeneration of the cholinergic system plays an important role in cognitive impairment during the preclinical stage of Alzheimer's disease, which may provide a significant target for early therapeutic interventions.

Associations of Alzheimer's Disease Pathology and Small Vessel Disease With Cerebral White Matter Degeneration: A Tract-Based MR Diffusion Imaging Study.

BACKGROUND: White matter (WM) degeneration is a key feature of Alzheimer's disease (AD). However, the underlying mechanism remains unclear. PURPOSE: To investigate how amyloid-ß (Aß), tau, and small vascular disease (SVD) jointly affect WM degeneration in subjects along AD continuum. STUDY TYPE: Retrospective. SUBJECTS: 152 non-demented participants (age: 55.8-91.6, male/female: 66/86) from the ADNI database were included, classified into three groups using the A (Aß)/T (tau)/N pathological scheme (Group 1: A-T-; Group 2: A+T-; Group 3: A+T+) based on positron emission tomography data. FIELD STRENGTH/SEQUENCE: 3T; T1-weighted images, T2-weighted fluid-attenuated inversion recovery images, T2*-weighted images, diffusion-weighted spin-echo echo-planar imaging sequence (54 diffusion directions). ASSESSMENT: Free-water diffusion model (generated parameters: free water, FW; tissue fractional anisotropy, FAt; tissue mean diffusivity, MDt); SVD total score; Neuropsychological tests. STATISTICAL TESTS: Linear regression analysis was performed to investigate the independent contribution of AD (Aß and tau) and SVD pathologies to diffusion parameters in each fiber tract, first in the entire population and then in each subgroup. We also investigated associations between diffusion parameters and cognitive functions. The level of statistical significance was set at p < 0.05 (false discovery rate corrected). RESULTS: In the entire population, we found that: 1) Increased FW was significantly associated with SVD and tau, while FAt and MDt were significantly associated with Aß and tau; 2) The spatial pattern of fiber tracts related to a certain pathological marker is consistent with the known distribution of that pathology; 3) Subgroup analysis showed that Group 2 and 3 had more alterations of FAt and MDt associated with Aß and tau; 4) Diffusion imaging indices showed significant associations with cognitive score in all domains except memory. DATA CONCLUSION: WM microstructural injury was associated with both AD and SVD pathologies, showing compartment-specific, tract-specific, and stage-specific WM patterns. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.

Decoupling of Regional Cerebral Blood Flow and Brain Function Along the Alzheimer's Disease Continuum.

BACKGROUND: Alzheimer's disease (AD) is accompanied with impaired neurovascular coupling. However, its early alteration remains elusive along the AD continuum. OBJECTIVE: This study aimed to investigate the early disruption of neurovascular coupling in cognitively normal (CN) and mild cognitive impairment (MCI) elderly and its association with cognition and AD pathologies. METHODS: We included 43 amyloid-ß-negative CN participants and 38 amyloid-ß-positive individuals (18 CN and 20 MCI) from the Alzheimer's Disease Neuroimaging Initiative dataset. Regional homogeneity (ReHo) map was used to represent neuronal activity and cerebral blood flow (CBF) map was used to represent cerebral blood perfusion. Neurovascular coupling was assessed by CBF/ReHo ratio at the voxel level. Analyses of covariance to detect the between-group differences and to further investigate the relations between CBF/ReHo ratio and AD biomarkers or cognition. In addition, the correlation of cerebral small vessel disease (SVD) burden and neurovascular coupling was assessed as well. RESULTS: Related to amyloid-ß-negative CN group, amyloid-ß-positive groups showed decreased CBF/ReHo ratio mainly in the left medial and inferior temporal gyrus. Furthermore, lower CBF/ReHo ratio was associated with a lower Mini-Mental State Examination score as well as higher AD pathological burden. No association between CBF/ReHo ratio and SVD burden was observed. CONCLUSION: AD pathology is a major correlate of the disturbed neurovascular coupling along the AD continuum, independent of SVD pathology. The CBF/ReHo ratio may be an index for detecting neurovascular coupling abnormalities, which could be used for early diagnosis in the future.

Distinct cerebral small vessel disease impairment in early- and late-onset Alzheimer's disease.

OBJECTIVE: This study investigated cerebral small vessel disease (CSVD) damage patterns in early-onset and late-onset Alzheimer's disease (EOAD and LOAD) and their effects on cognitive function. METHODS: This study included 93 participants, 45 AD patients (14 EOAD and 31 LOAD), and 48 normal controls (13 YNC and 35 ONC) from the ADNI database. All participants had diffusion tensor imaging data; some had amyloid PET and plasma p-tau181 data. The study used peak width of skeletonized mean diffusivity (PSMD) to measure CSVD severity and compared PSMD between patients and age-matched controls. The effect of age on the relationship between PSMD and cognition was also examined. The study also repeated the analysis in amyloid-positive AD patients and amyloid-negative controls in another independent database (31 EOAD and 38 LOAD), and the merged database. RESULTS: EOAD and LOAD showed similar cognitive function and disease severity. PSMD was validated as a reliable correlate of cognitive function. In the ADNI database, PSMD was significantly higher for LOAD and showed a tendency to increase for EOAD; in the independent and merged databases, PSMD was significantly higher for both LOAD and EOAD. The impact of PSMD on cognitive function was notably greater in the younger group (YNC and EOAD) than in the older group (ONC and LOAD), as supported by the ADNI and merged databases. INTERPRETATION: EOAD has less CSVD burden than LOAD, but has a greater impact on cognition. Proactive cerebrovascular prevention strategies may have potential clinical value for younger older adults with cognitive decline.

Distinct resting-state functional connectivity patterns of Anterior Insula affected by smoking in mild cognitive impairment.

Smoking is a modifiable risk factor for Alzheimer's disease (AD). The insula plays a vital role in both smoking and cognition. However, the smoking effects on insula-related networks in cognitively normal controls (CN) and mild cognitive impairment (MCI) patients remain unknown. We identified 129 CN (85 non-smokers and 44 smokers) and 83 MCI (54 non-smokers and 29 smokers). Each underwent neuropsychological assessment and MRI (structural and resting-state functional). Seed-based functional analyses in the anterior and posterior insula were performed to calculate the functional connectivity (FC) with voxels in the whole brain. Mixed-effect analyses were performed to explore the interactive effects on smoking and cognitive status. Associations between FC and neuropsychological scales were assessed. Mixed-effect analyses revealed the FC differences between the right anterior insula (RAI) with the left middle temporal gyrus (LMTG) and that with the right inferior parietal lobule (RIPL) (p < 0.01, cluster level < 0.05, two-tailed, gaussian random field correction). The FC of RAI in both LMTG and RIPL sees a significant decrease in MCI smokers (p < 0.01). Smoking affects insula FC differently between MCI and CN, and could decrease the insula FC in MCI patients. Our study provides evidence of neural mechanisms between smoking and AD.

Increased iron deposition in nucleus accumbens associated with disease progression and chronicity in migraine.

BACKGROUND: Migraine is one of the world's most prevalent and disabling diseases. Despite huge advances in neuroimaging research, more valuable neuroimaging markers are still urgently needed to provide important insights into the brain mechanisms that underlie migraine symptoms. We therefore aim to investigate the regional iron deposition in subcortical nuclei of migraineurs as compared to controls and its association with migraine-related pathophysiological assessments. METHODS: A total of 200 migraineurs (56 chronic migraine [CM], 144 episodic migraine [EM]) and 41 matched controls were recruited. All subjects underwent MRI and clinical variables including frequency/duration of migraine, intensity of migraine, 6-item Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS), and Pittsburgh Sleep Quality Index (PSQI) were recorded. Quantitative susceptibility mapping was employed to quantify the regional iron content in subcortical regions. Associations between clinical variables and regional iron deposition were studied as well. RESULTS: Increased iron deposition in the putamen, caudate, and nucleus accumbens (NAC) was observed in migraineurs more than controls. Meanwhile, patients with CM had a significantly higher volume of iron deposits compared to EM in multiple subcortical nuclei, especially in NAC. Volume of iron in NAC can be used to distinguish patients with CM from EM with a sensitivity of 85.45% and specificity of 71.53%. As the most valuable neuroimaging markers in all of the subcortical nuclei, higher iron deposition in NAC was significantly associated with disease progression, and higher HIT-6, MIDAS, and PSQI. CONCLUSIONS: These findings provide evidence that iron deposition in NAC may be a biomarker for migraine chronicity and migraine-related dysfunctions, thus may help to understand the underlying vascular and neural mechanisms of migraine. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT04939922.

Inferior Frontal Sulcal Hyperintensity on FLAIR is Associated with Small Vessel Disease but not Alzheimer's Pathology.

BACKGROUND: The inferior frontal sulci are essential sites on the route of cerebrospinal fluid outflow. A recent study suggests that inferior frontal sulcal hyperintensities (IFSH) on FLAIR images might be related to glymphatic dysfunction. OBJECTIVE: To investigate whether IFSH is associated with Alzheimer's disease (AD) pathology and cerebral small vessel disease (SVD) burden. METHODS: We retrospectively collected data from 272 non-demented subjects in the ADNI3 database. The IFSH was assessed on 3D fluid-attenuated inversion recovery images. The standardized uptake value ratios of amyloid and tau PET were used to reflect the AD pathology burden. To measure the SVD burden, we assessed white matter hyperintensities (WMH), dilation of perivascular spaces, microbleeds, and lacunes. Finally, we performed ordinal logistic regression analyses to investigate the associations between the IFSH score and AD pathology and SVD burden. RESULTS: The IFSH score was associated with the deep WMH score (OR, 1.79; 95% CI, 1.24 - 2.59) controlling for age and sex. The association remained significant in the multivariable regression models. There was no association between the IFSH score and AD pathology burden. CONCLUSION: This study suggests that the IFSH sign is associated with SVD but not AD pathology. Further studies are needed to confirm the findings.