RÉSUMÉ
INTRODUCTION: Emerging evidence illustrates that temporal lobe epilepsy (TLE) involves network disruptions represented by hyperexcitability and other seizure-related neural plasticity. However, these associations are not well-characterized. Our study characterizes the whole brain white matter connectome abnormalities in TLE patients compared to healthy controls (HCs) from the prospective Epilepsy Connectome Project study. Furthermore, we assessed whether aberrant white matter connections are differentially related to cognitive impairment and a history of focal-to-bilateral tonic-clonic (FBTC) seizures. METHODS: Multi-shell connectome MRI data were preprocessed using the DESIGNER guidelines. The IIT Destrieux gray matter atlas was used to derive the 162 × 162 structural connectivity matrices (SCMs) using MRTrix3. ComBat data harmonization was applied to harmonize the SCMs from pre- and post-scanner upgrade acquisitions. Threshold-free network-based statistics were used for statistical analysis of the harmonized SCMs. Cognitive impairment status and FBTC seizure status were then correlated with these findings. RESULTS: We employed connectome measurements from 142 subjects, including 92 patients with TLE (36 males, mean age = 40.1 ± 11.7 years) and 50 HCs (25 males, mean age = 32.6 ± 10.2 years). Our analysis revealed overall significant decreases in cross-sectional area (CSA) of the white matter tract in TLE group compared to controls, indicating decreased white matter tract integrity and connectivity abnormalities in addition to apparent differences in graph theoretic measures of connectivity and network-based statistics. Focal and generalized cognitive impaired TLE patients showcased higher trend-level abnormalities in the white matter connectome via decreased CSA than those with no cognitive impairment. Patients with a positive FBTC seizure history also showed trend-level findings of association via decreased CSA. CONCLUSIONS: Widespread global aberrant white matter connectome changes were observed in TLE patients and characterized by seizure history and cognitive impairment, laying a foundation for future studies to expand on and validate the novel biomarkers and further elucidate TLE's impact on brain plasticity.
Sujet(s)
Connectome , Épilepsie temporale , Imagerie par résonance magnétique , Substance blanche , Humains , Épilepsie temporale/imagerie diagnostique , Épilepsie temporale/physiopathologie , Épilepsie temporale/anatomopathologie , Mâle , Substance blanche/imagerie diagnostique , Substance blanche/anatomopathologie , Femelle , Adulte , Adulte d'âge moyen , Dysfonctionnement cognitif/physiopathologie , Dysfonctionnement cognitif/imagerie diagnostique , Dysfonctionnement cognitif/étiologie , Dysfonctionnement cognitif/anatomopathologie , Réseau nerveux/imagerie diagnostique , Réseau nerveux/physiopathologie , Réseau nerveux/anatomopathologie , Études prospectives , Encéphale/imagerie diagnostique , Encéphale/anatomopathologie , Encéphale/physiopathologieRÉSUMÉ
The aggregation and prion-like propagation of tau are the hallmarks of Alzheimer's disease (AD) and other tauopathies. However, the molecular mechanisms underlying the assembly and spread of tau pathology remain elusive. Epidemiological data show that exposure to fine particulate matter (PM2.5) is associated with an increased risk of AD. However, the molecular mechanisms remain unknown. Here, we showed that PM2.5 triggered the aggregation of tau and promoted the formation of tau fibrils. Injection of PM2.5-induced tau preformed fibrils (PFFs) into the hippocampus of tau P301S transgenic mice promoted the aggregation of tau and induced cognitive deficits and synaptic dysfunction. Furthermore, intranasal administration of PM2.5 exacerbated tau pathology and induced cognitive impairment in tau P301S mice. In conclusion, our results indicated that PM2.5 exposure promoted tau pathology and induced cognitive impairments. These results provide mechanistic insight into how PM2.5 increases the risk of AD.
Sujet(s)
Modèles animaux de maladie humaine , Hippocampe , Souris transgéniques , Matière particulaire , Tauopathies , Protéines tau , Animaux , Matière particulaire/toxicité , Protéines tau/métabolisme , Souris , Tauopathies/métabolisme , Tauopathies/anatomopathologie , Hippocampe/métabolisme , Hippocampe/anatomopathologie , Hippocampe/effets des médicaments et des substances chimiques , Dysfonctionnement cognitif/métabolisme , Dysfonctionnement cognitif/induit chimiquement , Dysfonctionnement cognitif/anatomopathologie , Maladie d'Alzheimer/métabolisme , Maladie d'Alzheimer/anatomopathologie , Maladie d'Alzheimer/induit chimiquement , Maladie d'Alzheimer/étiologie , Agrégation pathologique de protéines/métabolisme , Humains , MâleRÉSUMÉ
BACKGROUND: The cholinergic neurotransmitter system is crucial to cognitive function, with the basal forebrain (BF) being particularly susceptible to Alzheimer's disease (AD) pathology. However, the interaction of white matter hyperintensities (WMH) in cholinergic pathways and BF atrophy without amyloid pathology remains poorly understood. METHODS: We enrolled patients who underwent neuropsychological tests, magnetic resonance imaging, and 18F-florbetaben positron emission tomography due to cognitive impairment at the teaching university hospital from 2015 to 2022. Among these, we selected patients with negative amyloid scans and additionally excluded those with Parkinson's dementia that may be accompanied by BF atrophy. The WMH burden of cholinergic pathways was quantified by the Cholinergic Pathways Hyperintensities Scale (CHIPS) score, and categorized into tertile groups because the CHIPS score did not meet normal distribution. Segmentation of the BF on volumetric T1-weighted MRI was performed using FreeSurfer, then was normalized for total intracranial volume. Multivariable regression analysis was performed to investigate the association between BF volumes and CHIPS scores. RESULTS: A total of 187 patients were enrolled. The median CHIPS score was 12 [IQR 5.0; 24.0]. The BF volume of the highest CHIPS tertile group (mean ± SD, 3.51 ± 0.49, CHIPSt3) was significantly decreased than those of the lower CHIPS tertile groups (3.75 ± 0.53, CHIPSt2; 3.83 ± 0.53, CHIPSt1; P = 0.02). In the univariable regression analysis, factors showing significant associations with the BF volume were the CHIPSt3 group, age, female, education, diabetes mellitus, smoking, previous stroke history, periventricular WMH, and cerebral microbleeds. In multivariable regression analysis, the CHIPSt3 group (standardized beta [ßstd] = -0.25, P = 0.01), female (ßstd = 0.20, P = 0.04), and diabetes mellitus (ßstd = -0.22, P < 0.01) showed a significant association with the BF volume. Sensitivity analyses showed a negative correlation between CHIPS score and normalized BF volume, regardless of WMH severity. CONCLUSIONS: We identified a significant correlation between strategic WMH burden in the cholinergic pathway and BF atrophy independently of amyloid positivity and WMH severity. These results suggest a mechanism of cholinergic neuronal loss through the dying-back phenomenon and provide a rationale that strategic WMH assessment may help identify target groups that may benefit from acetylcholinesterase inhibitor treatment.
Sujet(s)
Prosencéphale basal , Imagerie par résonance magnétique , Tomographie par émission de positons , Substance blanche , Humains , Femelle , Mâle , Sujet âgé , Substance blanche/imagerie diagnostique , Substance blanche/anatomopathologie , Prosencéphale basal/imagerie diagnostique , Prosencéphale basal/anatomopathologie , Adulte d'âge moyen , Tests neuropsychologiques , Dysfonctionnement cognitif/imagerie diagnostique , Dysfonctionnement cognitif/anatomopathologie , Dysfonctionnement cognitif/métabolisme , Atrophie/anatomopathologie , Sujet âgé de 80 ans ou plusRÉSUMÉ
BACKGROUND: Vascular mild cognitive impairment (VMCI) is a transitional condition that may evolve into Vascular Dementia(VaD). Hippocampal volume (HV) is suggested as an early marker for VaD, the role of white matter lesions (WMLs) in neurodegeneration remains debated. OBJECTIVES: Evaluate HV and WMLs as predictive markers of VaD in VMCI patients by assessing: (i)baseline differences in HV and WMLs between converters to VaD and non-converters, (ii) predictive power of HV and WMLs for VaD, (iii) associations between HV, WMLs, and cognitive decline, (iv)the role of WMLs on HV. METHODS: This longitudinal multicenter study included 110 VMCI subjects (mean age:74.33 ± 6.63 years, 60males/50females) from the VMCI-Tuscany Study database. Subjects underwent brain MRI and cognitive testing, with 2-year follow-up data on VaD progression. HV and WMLs were semi-automatically segmented and measured. ANCOVA assessed group differences, while linear and logistic regression models evaluated predictive power. RESULTS: After 2 years, 32/110 VMCI patients progressed to VaD. Converting patients had lower HV(p = 0.015) and higher lesion volumes in the posterior thalamic radiation (p = 0.046), splenium of the corpus callosum (p = 0.016), cingulate gyrus (p = 0.041), and cingulum hippocampus(p = 0.038). HV alone did not fully explain progression (p = 0.059), but combined with WMLs volume, the model was significant (p = 0.035). The best prediction model (p = 0.001) included total HV (p = 0.004) and total WMLs volume of the posterior thalamic radiation (p = 0.005) and cingulate gyrus (p = 0.005), achieving 80% precision, 81% specificity, and 74% sensitivity. Lower HV were linked to poorer performance on the Rey Auditory-Verbal Learning Test delayed recall (RAVLT) and Mini Mental State Examination (MMSE). CONCLUSIONS: HV and WMLs are significant predictors of progression from VMCI to VaD. Lower HV correlate with worse cognitive performance on RAVLT and MMSE tests.
Sujet(s)
Atrophie , Dysfonctionnement cognitif , Démence vasculaire , Évolution de la maladie , Hippocampe , Imagerie par résonance magnétique , Substance blanche , Humains , Mâle , Femelle , Dysfonctionnement cognitif/imagerie diagnostique , Dysfonctionnement cognitif/anatomopathologie , Dysfonctionnement cognitif/étiologie , Sujet âgé , Hippocampe/anatomopathologie , Hippocampe/imagerie diagnostique , Substance blanche/imagerie diagnostique , Substance blanche/anatomopathologie , Études longitudinales , Atrophie/anatomopathologie , Démence vasculaire/imagerie diagnostique , Démence vasculaire/anatomopathologie , Sujet âgé de 80 ans ou plus , Tests neuropsychologiquesRÉSUMÉ
BACKGROUND: Obstructive sleep apnoea (OSA) is a sleep-disordered breathing characterized by intermittent hypoxia (IH) that may cause cognitive dysfunction. However, the impact of IH on molecular processes involved in cognitive function remains unclear. METHODS: C57BL / 6 J mice were exposed to either normoxia (control) or IH for 6 weeks. DNA hydroxymethylation was quantified by hydroxymethylated DNA immunoprecipitation (hMeDIP) sequencing. ten-eleven translocation 1 (Tet1) was knocked down by lentivirus. Specifically, cognitive function was assessed by behavioral experiments, pathological features were assessed by HE staining, the hippocampal DNA hydroxymethylation was examined by DNA dot blot and immunohistochemical staining, while the Wnt signaling pathway and its downstream effects were studied using qRT-PCR, immunofluorescence staining, and Luminex liquid suspension chip analysis. RESULTS: IH mice showed pathological changes and cognitive dysfunction in the hippocampus. Compared with the control group, IH mice exhibited global DNA hydroxylmethylation in the hippocampus, and the expression of three hydroxylmethylases increased significantly. The Wnt signaling pathway was activated, and the mRNA and 5hmC levels of Wnt3a, Ccnd2, and Prickle2 were significantly up-regulated. Further caused downstream neurogenesis abnormalities and neuroinflammatory activation, manifested as increased expression of IBA1 (a marker of microglia), GFAP (a marker of astrocytes), and DCX (a marker of immature neurons), as well as a range of inflammatory cytokines (e.g. TNFa, IL3, IL9, and IL17A). After Tet1 knocked down, the above indicators return to normal. CONCLUSION: Activation of Wnt signaling pathway by hippocampal Tet1 is associated with cognitive dysfunction induced by IH.
Sujet(s)
Dysfonctionnement cognitif , Hippocampe , Souris de lignée C57BL , Protéines proto-oncogènes , Syndrome d'apnées obstructives du sommeil , Voie de signalisation Wnt , Animaux , Hippocampe/métabolisme , Hippocampe/anatomopathologie , Souris , Protéines proto-oncogènes/métabolisme , Protéines proto-oncogènes/génétique , Voie de signalisation Wnt/physiologie , Dysfonctionnement cognitif/métabolisme , Dysfonctionnement cognitif/anatomopathologie , Dysfonctionnement cognitif/étiologie , Syndrome d'apnées obstructives du sommeil/métabolisme , Syndrome d'apnées obstructives du sommeil/complications , Syndrome d'apnées obstructives du sommeil/anatomopathologie , Mâle , Maladies neuro-inflammatoires/métabolisme , Maladies neuro-inflammatoires/anatomopathologie , 5-Méthyl-cytosine/analogues et dérivés , 5-Méthyl-cytosine/métabolisme , Méthylation de l'ADN , Protéines de liaison à l'ADNRÉSUMÉ
BACKGROUND: The volumes of the hippocampal subfields are related to poststroke cognitive dysfunctions. However, it remains unclear whether contralesional hippocampal subfield volume contributes to cognitive impairment. This study aimed to investigate the volumetric differences in the contralesional hippocampal subfields between patients with left and right hemisphere strokes (LHS/RHS). Additionally, correlations between contralesional hippocampal subfield volumes and clinical outcomes were explored. METHODS: Fourteen LHS (13 males, 52.57 ± 7.10 years), 13 RHS (11 males, 51.23 ± 15.23 years), and 18 healthy controls (11 males, 46.94 ± 12.74 years) were enrolled. Contralesional global and regional hippocampal volumes were obtained with T1-weighted images. Correlations between contralesional hippocampal subfield volumes and clinical outcomes, including the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE), were analyzed. Bonferroni correction was applied for multiple comparisons. RESULTS: Significant reductions were found in contralesional hippocampal as a whole (adjusted p = .011) and its subfield volumes, including the hippocampal tail (adjusted p = .005), cornu ammonis 1 (CA1) (adjusted p = .002), molecular layer (ML) (adjusted p = .004), granule cell and ML of the dentate gyrus (GC-ML-DG) (adjusted p = .015), CA3 (adjusted p = .009), and CA4 (adjusted p = .014) in the RHS group compared to the LHS group. MoCA and MMSE had positive correlations with volumes of contralesional hippocampal tail (p = .015, r = .771; p = .017, r = .763) and fimbria (p = .020, r = .750; p = .019, r = .753) in the LHS group, and CA3 (p = .007, r = .857; p = .009, r = .838) in the RHS group, respectively. CONCLUSION: Unilateral stroke caused volumetric differences in different hippocampal subfields contralesionally, which correlated to cognitive impairment. RHS leads to greater volumetric reduction in the whole contralesional hippocampus and specific subfields (hippocampal tail, CA1, ML, GC-ML-DG, CA3, and CA4) compared to LHS. These changes are correlated with cognitive impairments, potentially due to disrupted neural pathways and interhemispheric communication.
Sujet(s)
Dysfonctionnement cognitif , Hippocampe , Imagerie par résonance magnétique , Accident vasculaire cérébral , Humains , Mâle , Adulte d'âge moyen , Femelle , Hippocampe/anatomopathologie , Hippocampe/imagerie diagnostique , Accident vasculaire cérébral/imagerie diagnostique , Accident vasculaire cérébral/anatomopathologie , Adulte , Dysfonctionnement cognitif/imagerie diagnostique , Dysfonctionnement cognitif/anatomopathologie , Dysfonctionnement cognitif/physiopathologie , Dysfonctionnement cognitif/étiologie , Latéralité fonctionnelle/physiologie , Cognition/physiologie , Sujet âgé , Tests de l'état mental et de la démenceRÉSUMÉ
Vascular dementia (VaD) is a prevalent form of dementia resulting from chronic cerebral hypoperfusion (CCH). However, the pathogenic mechanisms of VaD and corresponding therapeutic strategies are not well understood. Sirtuin 6 (SIRT6) has been implicated in various biological processes, including cellular metabolism, DNA repair, redox homeostasis, and aging. Nevertheless, its functional relevance in VaD remains unexplored. In this study, we utilized a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate the role of SIRT6. We detected a significant decrease in neuronal SIRT6 protein expression following CCH. Intriguingly, neuron-specific ablation of Sirt6 in mice exacerbated neuronal damage and cognitive deficits after CCH. Conversely, treatment with MDL-800, an agonist of SIRT6, effectively mitigated neuronal loss and facilitated neurological recovery. Mechanistically, SIRT6 inhibited excessive mitochondrial fission by suppressing the CCH-induced STAT5-PGAM5-Drp1 signaling cascade. Additionally, the gene expression of monocyte SIRT6 in patients with asymptomatic carotid stenosis showed a correlation with cognitive outcomes, suggesting translational implications in human subjects. Our findings provide the first evidence that SIRT6 prevents cognitive impairment induced by CCH, and mechanistically, this protection is achieved through the remodeling of mitochondrial dynamics in a STAT5-PGAM5-Drp1-dependent manner.
Sujet(s)
Dysfonctionnement cognitif , Dynamines , Dynamique mitochondriale , Facteur de transcription STAT-5 , Sirtuines , Animaux , Sirtuines/métabolisme , Sirtuines/génétique , Dynamique mitochondriale/effets des médicaments et des substances chimiques , Dysfonctionnement cognitif/anatomopathologie , Humains , Dynamines/métabolisme , Dynamines/génétique , Mâle , Facteur de transcription STAT-5/métabolisme , Souris de lignée C57BL , Neurones/métabolisme , Neurones/effets des médicaments et des substances chimiques , Neurones/anatomopathologie , Transduction du signal/effets des médicaments et des substances chimiques , Sténose carotidienne/complications , Sténose carotidienne/métabolisme , Maladie chronique , Souris , Encéphalopathie ischémique/complications , Encéphalopathie ischémique/anatomopathologie , Encéphalopathie ischémique/métabolismeRÉSUMÉ
Few population-based studies including younger adults have examined the potential of olfactory function tests to capture the degree of atrophy in memory-associated brain regions, which cannot be adequately explained by cognitive function tests screening for cognitive impairment. This population-based study investigated associations between high-resolution olfactory test data with few odours and grey matter volumes (GMVs) of the left and right hippocampi, amygdala, parahippocampi, and olfactory cortex, while accounting for differences in cognitive decline, in 1444 participants (aged 31-91 years). Regression analyses included intracranial volume (ICV)-normalised GMVs of eight memory-related regions as objective variables and age, sex, education duration, smoking history, olfaction test score, and the Montreal Cognitive Assessment-Japanese version (MoCA-J) score as explanatory variables. Significant relationships were found between olfactory test scores and ICV-normalised GMVs of the left and right hippocampi and left amygdala (p = 0.020, 0.024, and 0.028, respectively), adjusting for the MoCA-J score. The olfactory test score was significantly related to the right amygdalar GMV (p = 0.020) in older adults (age ≥ 65 years). These associations remained significant after applying Benjamini-Hochberg multiple testing correction (false discovery rate < 0.1). Therefore, olfactory and cognitive function tests may efficiently capture the degree of atrophy in the hippocampi and amygdala, especially in older adults.
Sujet(s)
Amygdale (système limbique) , Cognition , Substance grise , Hippocampe , Imagerie par résonance magnétique , Humains , Sujet âgé , Mâle , Femelle , Adulte d'âge moyen , Études transversales , Substance grise/imagerie diagnostique , Substance grise/anatomopathologie , Amygdale (système limbique)/anatomopathologie , Amygdale (système limbique)/imagerie diagnostique , Hippocampe/anatomopathologie , Hippocampe/imagerie diagnostique , Sujet âgé de 80 ans ou plus , Cognition/physiologie , Adulte , Imagerie par résonance magnétique/méthodes , Dysfonctionnement cognitif/anatomopathologie , Dysfonctionnement cognitif/diagnostic , Dysfonctionnement cognitif/imagerie diagnostique , Tests neuropsychologiques , Atrophie , Odorat/physiologie , Taille d'organeRÉSUMÉ
Prolonged ventricular repolarization has been associated with cardiovascular disease. We sought to investigate the association of prolonged ventricular repolarization with mild cognitive impairment (MCI) and the potential underlying neuropathological mechanisms in older adults. This cross-sectional study included 4328 dementia-free participants (age ≥ 65 years; 56.8% female) in the baseline examination of the Multidomain INterventions to delay dementia and Disability in rural China; of these, 989 undertook structural brain magnetic resonance imaging (MRI) scans. QT, QTc, JT, JTc, and QRS intervals were derived from 12-lead electrocardiograph. MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) were defined following the Petersen's criteria. Volumes of gray matter (GM), white matter, cerebrospinal fluid, total white matter hyperintensities (WMH), periventricular WMH (PWMH), and deep WMH (DWMH) were automatically estimated. Data were analyzed using logistic and general linear regression models. Prolonged QT, QTc, JT, and JTc intervals were significantly associated with an increased likelihood of MCI and aMCI, but not naMCI (p < 0.05). In the MRI subsample, QT, QTc, JT, and JTc intervals were significantly associated with larger total WMH and PWMH volumes (p < 0.05), but not with DWMH volume. Statistical interactions were detected, such that prolonged QT and JT intervals were significantly associated with reduced GM volume only among participants with coronary heart disease or without APOE ε4 allele (p < 0.05). Prolonged ventricular repolarization is associated with MCI and cerebral microvascular lesions in a general population of older adults. This underlies the importance of cognitive assessments and brain MRI examination among older adults with prolonged QT interval.
Sujet(s)
Dysfonctionnement cognitif , Imagerie par résonance magnétique , Substance blanche , Humains , Dysfonctionnement cognitif/physiopathologie , Dysfonctionnement cognitif/imagerie diagnostique , Dysfonctionnement cognitif/anatomopathologie , Femelle , Mâle , Sujet âgé , Études transversales , Substance blanche/imagerie diagnostique , Substance blanche/anatomopathologie , Substance blanche/physiopathologie , Imagerie par résonance magnétique/méthodes , Électrocardiographie , Sujet âgé de 80 ans ou plus , Substance grise/imagerie diagnostique , Substance grise/anatomopathologie , Substance grise/physiopathologie , ChineRÉSUMÉ
As a potential preclinical stage of Alzheimer's dementia, subjective cognitive decline (SCD) reveals a higher risk of future cognitive decline and conversion to dementia. However, it has not been clear whether SCD status increases the clinical progression of older adults in the context of amyloid deposition, cerebrovascular disease (CeVD), and psychiatric symptoms. We identified 99 normal controls (NC), 15 SCD individuals who developed mild cognitive impairment in the next 2 years (P-SCD), and 54 SCD individuals who did not (S-SCD) from ADNI database with both baseline and 2-year follow-up data. Total white matter hyperintensity (WMH), WMH in deep (DWMH) and periventricular (PWMH) regions, and voxel-wise grey matter volumes were compared among groups. Furthermore, using structural equation modelling method, we constructed path models to explore SCD-related brain changes longitudinally and to determine whether baseline SCD status, age, and depressive symptoms affect participants' clinical outcomes. Both SCD groups showed higher baseline amyloid PET SUVR, baseline PWMH volumes, and larger increase of PWMH volumes over time than NC. In contrast, only P-SCD had higher baseline DWMH volumes and larger increase of DWMH volumes over time than NC. No longitudinal differences in grey matter volume and amyloid was observed among NC, S-SCD, and P-SCD. Our path models demonstrated that SCD status contributed to future WMH progression. Further, baseline SCD status increases the risk of future cognitive decline, mediated by PWMH; baseline depressive symptoms directly contribute to clinical outcomes. In conclusion, both S-SCD and P-SCD exhibited more severe CeVD than NC. The CeVD burden increase was more pronounced in P-SCD. In contrast with the direct association of depressive symptoms with dementia severity progression, the effects of SCD status on future cognitive decline may manifest via CeVD pathologies. Our work highlights the importance of multi-modal longitudinal designs in understanding the SCD trajectory heterogeneity, paving the way for stratification and early intervention in the preclinical stage. PRACTITIONER POINTS: Both S-SCD and P-SCD exhibited more severe CeVD at baseline and a larger increase of CeVD burden compared to NC, while the burden was more pronounced in P-SCD. Baseline SCD status increases the risk of future PWMH and DWMH volume accumulation, mediated by baseline PWMH and DWMH volumes, respectively. Baseline SCD status increases the risk of future cognitive decline, mediated by baseline PWMH, while baseline depression status directly contributes to clinical outcome.
Sujet(s)
Dysfonctionnement cognitif , Évolution de la maladie , Imagerie par résonance magnétique , Tomographie par émission de positons , Humains , Dysfonctionnement cognitif/imagerie diagnostique , Dysfonctionnement cognitif/anatomopathologie , Dysfonctionnement cognitif/physiopathologie , Dysfonctionnement cognitif/étiologie , Femelle , Mâle , Sujet âgé , Substance grise/imagerie diagnostique , Substance grise/anatomopathologie , Sujet âgé de 80 ans ou plus , Encéphale/imagerie diagnostique , Encéphale/anatomopathologie , Substance blanche/imagerie diagnostique , Substance blanche/anatomopathologie , Études longitudinales , Auto-évaluation diagnostique , Dépression/imagerie diagnostique , Dépression/anatomopathologieRÉSUMÉ
Reactive astrocytes are associated with neuroinflammation and cognitive decline in diverse neuropathologies; however, the underlying mechanisms are unclear. We used optogenetic and chemogenetic tools to identify the crucial roles of the hippocampal CA1 astrocytes in cognitive decline. Our results showed that repeated optogenetic stimulation of the hippocampal CA1 astrocytes induced cognitive impairment in mice and decreased synaptic long-term potentiation (LTP), which was accompanied by the appearance of inflammatory astrocytes. Mechanistic studies conducted using knockout animal models and hippocampal neuronal cultures showed that lipocalin-2 (LCN2), derived from reactive astrocytes, mediated neuroinflammation and induced cognitive impairment by decreasing the LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes provided similar results. Conversely, these phenomena were attenuated by a metabolic inhibitor of astrocytes. Fiber photometry using GCaMP revealed a high level of hippocampal astrocyte activation in the neuroinflammation model. Our findings suggest that reactive astrocytes in the hippocampus are sufficient and required to induce cognitive decline through LCN2 release and synaptic modulation. This abnormal glial-neuron interaction may contribute to the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions.
Sujet(s)
Astrocytes , Dysfonctionnement cognitif , Hippocampe , Lipocaline-2 , Potentialisation à long terme , Maladies neuro-inflammatoires , Neurones , Animaux , Astrocytes/métabolisme , Astrocytes/anatomopathologie , Dysfonctionnement cognitif/métabolisme , Dysfonctionnement cognitif/étiologie , Dysfonctionnement cognitif/anatomopathologie , Lipocaline-2/métabolisme , Lipocaline-2/génétique , Souris , Hippocampe/métabolisme , Hippocampe/anatomopathologie , Maladies neuro-inflammatoires/anatomopathologie , Maladies neuro-inflammatoires/métabolisme , Neurones/métabolisme , Neurones/anatomopathologie , Souris knockout , Mâle , Souris de lignée C57BL , Récepteurs du N-méthyl-D-aspartate/métabolisme , Optogénétique , Région CA1 de l'hippocampe/anatomopathologie , Région CA1 de l'hippocampe/métabolisme , Modèles animaux de maladie humaineRÉSUMÉ
The emergence of sustained neuropsychiatric symptoms (NPS) among non-demented individuals in later life, defined as mild behavioral impairment (MBI), is linked to a higher risk of cognitive decline. However, the underlying pathophysiological mechanisms remain largely unexplored. A growing body of evidence has shown that MBI is associated with alterations in structural and functional neuroimaging studies, higher genetic predisposition to clinical diagnosis of Alzheimer's disease (AD), as well as amyloid and tau pathology assessed in the blood, cerebrospinal fluid, positron-emission tomography (PET) imaging and neuropathological examination. These findings shed more light on the MBI-related potential neurobiological mechanisms, paving the way for the development of targeted pharmacological approaches. In this review, we aim to discuss the available clinical evidence on the role of amyloid and tau pathology in MBI and the potential underlying pathophysiological mechanisms. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, disruption of neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF), abnormal neuroinflammatory responses including the kynurenine pathway, dysregulation of transforming growth factor beta (TGF-ß1), epigenetic alterations including micro-RNA (miR)-451a and miR-455-3p, synaptic dysfunction, imbalance in neurotransmitters including acetylcholine, dopamine, serotonin, gamma-aminobutyric acid (GABA) and norepinephrine, as well as altered locus coeruleus (LC) integrity are some of the potential mechanisms connecting MBI with amyloid and tau pathology. The elucidation of the underlying neurobiology of MBI would facilitate the design and efficacy of relative clinical trials, especially towards amyloid- or tau-related pathways. In addition, we provide insights for future research into our deeper understanding of its underlying pathophysiology of MBI, and discuss relative therapeutic implications.
Sujet(s)
Protéines tau , Humains , Protéines tau/métabolisme , Dysfonctionnement cognitif/métabolisme , Dysfonctionnement cognitif/anatomopathologie , Dysfonctionnement cognitif/physiopathologie , Maladie d'Alzheimer/métabolisme , Maladie d'Alzheimer/anatomopathologie , Animaux , Amyloïde/métabolisme , Peptides bêta-amyloïdes/métabolismeRÉSUMÉ
BACKGROUND AND OBJECTIVES: Amyloid pathology, vascular disease pathology, and pathologies affecting the medial temporal lobe are associated with cognitive trajectories in older adults. However, only limited evidence exists on how these pathologies influence cognition in the oldest old. We evaluated whether amyloid burden, white matter hyperintensity (WMH) volume, and hippocampal volume (HV) are associated with cognitive level and decline in the oldest old. METHODS: This was a longitudinal, observational community-based cohort study. We included participants with 18F-florbetapir PET and MRI data from the 90+ Study. Amyloid load was measured using the standardized uptake value ratio in the precuneus/posterior cingulate with eroded white matter mask as reference. WMH volume was log-transformed. All imaging measures were standardized using sample means and SDs. HV and log-WMH volume were normalized by total intracranial volume using the residual approach. Global cognitive performance was measured by the Mini-Mental State Examination (MMSE) and modified MMSE (3MS) tests, repeated every 6 months. We used linear mixed-effects models with random intercepts; random slopes; and interaction between time, time squared, and imaging variables to estimate the associations of imaging variables with cognitive level and cognitive decline. Models were adjusted for demographics, APOE genotype, and health behaviors. RESULTS: The sample included 192 participants. The mean age was 92.9 years, 125 (65.1%) were female, 71 (37.0%) achieved a degree beyond college, and the median follow-up time was 3.0 years. A higher amyloid load was associated with a lower cognitive level (ßMMSE = -0.82, 95% CI -1.17 to -0.46; ß3MS = -2.77, 95% CI -3.69 to -1.84). A 1-SD decrease in HV was associated with a 0.70-point decrease in the MMSE score (95% CI -1.14 to -0.27) and a 2.27-point decrease in the 3MS score (95% CI -3.40 to -1.14). Clear nonlinear cognitive trajectories were detected. A higher amyloid burden and smaller HV were associated with faster cognitive decline. WMH volume was not significantly associated with cognitive level or decline. DISCUSSION: Amyloid burden and hippocampal atrophy are associated with both cognitive level and cognitive decline in the oldest old. Our findings shed light on how different pathologies contributed to driving cognitive function in the oldest old.
Sujet(s)
Dysfonctionnement cognitif , Hippocampe , Imagerie par résonance magnétique , Tomographie par émission de positons , Substance blanche , Humains , Femelle , Mâle , Substance blanche/imagerie diagnostique , Substance blanche/anatomopathologie , Substance blanche/métabolisme , Hippocampe/imagerie diagnostique , Hippocampe/anatomopathologie , Hippocampe/métabolisme , Sujet âgé de 80 ans ou plus , Études longitudinales , Dysfonctionnement cognitif/imagerie diagnostique , Dysfonctionnement cognitif/anatomopathologie , Dysfonctionnement cognitif/métabolisme , Cognition/physiologie , Études de cohortes , Taille d'organe , Éthylène glycols , Dérivés de l'aniline , Peptides bêta-amyloïdes/métabolisme , Amyloïde/métabolismeRÉSUMÉ
BACKGROUND: Pathologic perivascular spaces (PVS), the fluid-filled compartments surrounding brain vasculature, may underlie cognitive decline in Parkinson's disease (PD). However, whether this impacts specific cognitive domains has not been investigated. OBJECTIVES: This study examined the relationship of PVS volume at baseline with domain-specific and global cognitive change over 2 years in PD individuals. METHODS: A total of 39 individuals with PD underwent 3T T1w magnetic resonance imaging to determine PVS volume fraction (PVS volume normalized to total regional volume) within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, and superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of cognitive domains and global cognitive function at baseline and after 2 years. RESULTS: Higher basal ganglia PVS at baseline was associated with greater decline in attention, executive function, and global cognition scores. CONCLUSIONS: While previous reports have associated elevated PVS volume in the basal ganglia with decline in global cognition in PD, our findings show such decline may affect the attention and executive function domains.
Sujet(s)
Attention , Noyaux gris centraux , Dysfonctionnement cognitif , Fonction exécutive , Imagerie par résonance magnétique , Maladie de Parkinson , Humains , Maladie de Parkinson/imagerie diagnostique , Maladie de Parkinson/anatomopathologie , Maladie de Parkinson/physiopathologie , Noyaux gris centraux/imagerie diagnostique , Noyaux gris centraux/anatomopathologie , Noyaux gris centraux/physiopathologie , Fonction exécutive/physiologie , Femelle , Mâle , Sujet âgé , Adulte d'âge moyen , Attention/physiologie , Dysfonctionnement cognitif/physiopathologie , Dysfonctionnement cognitif/étiologie , Dysfonctionnement cognitif/imagerie diagnostique , Dysfonctionnement cognitif/anatomopathologie , Système glymphatique/imagerie diagnostique , Système glymphatique/anatomopathologie , Système glymphatique/physiopathologie , Tests neuropsychologiques , Substance blanche/imagerie diagnostique , Substance blanche/anatomopathologie , Substance blanche/physiopathologieRÉSUMÉ
OBJECTIVE: Alzheimer's disease (AD) pathology is featured by the extracellular accumulation of amyloid-ß (Aß) plaques and intracellular tau neurofibrillary tangles in the brain. We studied whether Aß and tau accumulation are independently associated with future cognitive decline in the AD continuum. METHODS: Data were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI) public database. A total of 1272 participants were selected based on the availability of Aß-PET and CSF tau at baseline and of those 777 participants with follow-up visits. RESULTS: We found that Aß-PET and CSF tau pathology were related to cognitive decline across the AD clinical spectrum, both as potential predictors for dementia progression. Among them, Aß-PET (A + T- subjects) is an independent reliable predictor of longitudinal cognitive decline in terms of ADAS-13, ADNI-MEM, and MMSE scores rather than tau pathology (A - T+ subjects), indicating tau accumulation is not closely correlated with future cognitive impairment without being driven by Aß deposition. Of note, a high percentage of APOE ε4 carriers with Aß pathology (A+) develop poor memory and learning capacity. Interestingly, this condition is not recurrence in terms of the ADNI-MEM domain when adding APOE ε4 status. Finally, the levels of Aß-PET SUVR related to glucose hypometabolism more strongly in subjects with A + T- than A - T+ both happen at baseline and longitudinal changes. CONCLUSIONS: In conclusion, Aß-PET alone without tau pathology (A + T-) measure is an independent reliable predictor of longitudinal cognitive decline but may nonetheless forecast different status of dementia progression. However, tau accumulation alone without Aß pathology background (A - T+) was not enough to be an independent predictor of cognitive worsening.
Sujet(s)
Peptides bêta-amyloïdes , Dysfonctionnement cognitif , Tomographie par émission de positons , Protéines tau , Humains , Protéines tau/métabolisme , Femelle , Mâle , Peptides bêta-amyloïdes/métabolisme , Sujet âgé , Dysfonctionnement cognitif/métabolisme , Dysfonctionnement cognitif/imagerie diagnostique , Dysfonctionnement cognitif/anatomopathologie , Tomographie par émission de positons/tendances , Études longitudinales , Sujet âgé de 80 ans ou plus , Évolution de la maladie , Maladie d'Alzheimer/métabolisme , Maladie d'Alzheimer/anatomopathologie , Maladie d'Alzheimer/imagerie diagnostique , Maladie d'Alzheimer/psychologie , Adulte d'âge moyenRÉSUMÉ
BACKGROUND: Blood-brain barrier (BBB) alterations may contribute to AD pathology through various mechanisms, including impaired amyloid-ß (Aß) clearance and neuroinflammation. Soluble platelet-derived growth factor receptor beta (sPDGFRß) has emerged as a potential biomarker for BBB integrity. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers a direct assessment of BBB permeability. However, the relationship between BBB dysfunction, cognitive impairment, and AD pathology remains unclear, with inconsistent findings in the literature. METHODS: We conducted a cross-sectional study using data from the DELCODE and DESCRIBE cohorts to investigate BBB dysfunction in participants with normal cognition (NC), mild cognitive impairment (MCI), and AD dementia. BBB function was assessed using DCE-MRI and sPDGFRß levels in cerebrospinal fluid and AD biomarkers Aß and tau were measured. In a subset of patients, the CSF/plasma-ratio of albumin (QAlb) as a standard marker of BBB integrity and markers of neuroinflammation were analyzed. RESULTS: 91 participants (NC: 44, MCI: 21, AD: 26) were included in the analysis. The average age was 74.4 years, 42% were female. Increased hippocampal BBB disruption was observed in the AD-group (Ktrans: 0.55 × 10- 3 min- 1 ± 0.74 × 10- 3 min- 1) but not the MCI-group (Ktrans: 0.177 × 10- 3 min- 1 ± 0.22 × 10- 3 min- 1), compared to the NC group (Ktrans: 0.19 × 10- 3 min- 1 ± 0.37 × 10- 3 min- 1, p < .01). sPDGFRß was not significantly different between the cognitive groups. However, sPDGFRß levels were significantly associated with age (r = .33, p < .01), independent of vascular risk factors. Further, sPDGFRß showed significant positive associations with soluble Aß levels (Aß40: r = .57, p < .01; Aß42: r = .39, p < .01) and YKL-40 (r = .53, p < .01), a marker of neuroinflammation. sPDGFRß/DCE-MRI was not associated with overall AD biomarker positivity or APOE-status. CONCLUSION: In dementia, but not MCI, hippocampal BBB disruption was observed. sPDGFRß increased with age and was associated with neuroinflammation independent of cognitive impairment. The association between Aß and sPDGFRß may indicate a bidirectional relationship reflecting pericytes' clearance of soluble Aß and/or vasculotoxic properties of Aß.
Sujet(s)
Maladie d'Alzheimer , Peptides bêta-amyloïdes , Marqueurs biologiques , Barrière hémato-encéphalique , Dysfonctionnement cognitif , Imagerie par résonance magnétique , Maladies neuro-inflammatoires , Humains , Barrière hémato-encéphalique/anatomopathologie , Femelle , Dysfonctionnement cognitif/imagerie diagnostique , Dysfonctionnement cognitif/anatomopathologie , Mâle , Sujet âgé , Maladie d'Alzheimer/imagerie diagnostique , Maladie d'Alzheimer/anatomopathologie , Études transversales , Maladies neuro-inflammatoires/imagerie diagnostique , Maladies neuro-inflammatoires/anatomopathologie , Peptides bêta-amyloïdes/liquide cérébrospinal , Peptides bêta-amyloïdes/métabolisme , Marqueurs biologiques/liquide cérébrospinal , Marqueurs biologiques/sang , Adulte d'âge moyen , Sujet âgé de 80 ans ou plus , Récepteur au PDGF bêta/métabolisme , Protéines tau/liquide cérébrospinal , Protéines tau/métabolismeRÉSUMÉ
Women have a higher incidence of Alzheimer's disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify genes that underpin sex-associated risk of AD. PIN1 is a key regulator of the tau phosphorylation signaling pathway; however, potential differences in PIN1 expression, in males and females, are still unknown. We analyzed brain transcriptomic datasets focusing on sex differences in PIN1 mRNA levels in an aging and AD cohort, which revealed reduced PIN1 levels primarily within females. We validated this observation in an independent dataset (ROS/MAP), which also revealed that PIN1 is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function in females only. Additional analysis revealed a decrease in PIN1 in subjects with mild cognitive impairment (MCI) compared with aged individuals, again driven predominantly by female subjects. Histochemical analysis of PIN1 in AD and control male and female neocortex revealed an overall decrease in axonal PIN1 protein levels in females. These findings emphasize the importance of considering sex differences in AD research.
Sujet(s)
Maladie d'Alzheimer , Cognition , Dysfonctionnement cognitif , NIMA-interacting peptidylprolyl isomerase , Néocortex , Enchevêtrements neurofibrillaires , Caractères sexuels , Maladie d'Alzheimer/génétique , Maladie d'Alzheimer/anatomopathologie , Maladie d'Alzheimer/métabolisme , NIMA-interacting peptidylprolyl isomerase/génétique , NIMA-interacting peptidylprolyl isomerase/métabolisme , Humains , Femelle , Néocortex/anatomopathologie , Néocortex/métabolisme , Mâle , Dysfonctionnement cognitif/génétique , Dysfonctionnement cognitif/anatomopathologie , Dysfonctionnement cognitif/métabolisme , Sujet âgé , Sujet âgé de 80 ans ou plus , Enchevêtrements neurofibrillaires/anatomopathologie , Enchevêtrements neurofibrillaires/métabolisme , Phénotype , Système limbique/anatomopathologie , Système limbique/métabolisme , Expression des gènes , Vieillissement/anatomopathologie , Vieillissement/génétique , Vieillissement/métabolisme , ARN messager/métabolisme , ARN messager/génétique , Protéines tau/métabolisme , Protéines tau/génétique , PhosphorylationRÉSUMÉ
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder where pathophysiological changes begin decades before the onset of clinical symptoms. Analysis of brain atrophy patterns using structural MRI and multivariate data analysis are an effective tool in identifying patients with subjective cognitive decline (SCD) at higher risk of progression to AD dementia. Atrophy patterns obtained from models trained to classify advanced AD versus normal subjects, may not be optimal for subjects at an early stage, like SCD. In this study, we compared the accuracy of the SCD progression prediction using the 'severity index' generated using a standard classification model trained on patients with AD dementia versus a new model trained on ß-amyloid (Aß) positive patients with amnestic mild cognitive impairment (aMCI). METHODS: We used structural MRI data of 504 patients from the Swedish BioFINDER-1 study cohort (cognitively normal (CN), Aß-negative = 220; SCD, Aß positive and negative = 139; aMCI, Aß-positive = 106; AD dementia = 39). We applied multivariate data analysis to create two predictive models trained to discriminate CN individuals from either individuals with Aß positive aMCI or AD dementia. Models were applied to individuals with SCD to classify their atrophy patterns as either high-risk "disease-like" or low-risk "CN-like". Clinical trajectory and model accuracy were evaluated using 8 years of longitudinal data. RESULTS: In predicting progression from SCD to MCI or dementia, the standard, dementia-based model, reached 100% specificity but only 10.6% sensitivity, while the new, aMCI-based model, reached 72.3% sensitivity and 60.9% specificity. The aMCI-based model was superior in predicting progression from SCD to MCI or dementia, reaching a higher receiver operating characteristic area under curve (AUC = 0.72; P = 0.037) in comparison with the dementia-based model (AUC = 0.57). CONCLUSION: When predicting conversion from SCD to MCI or dementia using structural MRI data, prediction models based on individuals with milder levels of atrophy (i.e. aMCI) may offer superior clinical value compared to standard dementia-based models.
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Atrophie , Encéphale , Dysfonctionnement cognitif , Démence , Évolution de la maladie , Imagerie par résonance magnétique , Humains , Mâle , Femelle , Atrophie/anatomopathologie , Dysfonctionnement cognitif/imagerie diagnostique , Dysfonctionnement cognitif/anatomopathologie , Dysfonctionnement cognitif/diagnostic , Sujet âgé , Imagerie par résonance magnétique/méthodes , Encéphale/anatomopathologie , Encéphale/imagerie diagnostique , Démence/imagerie diagnostique , Démence/anatomopathologie , Adulte d'âge moyen , Sujet âgé de 80 ans ou plus , Études de cohortes , Tests neuropsychologiques , Maladie d'Alzheimer/imagerie diagnostique , Maladie d'Alzheimer/anatomopathologieRÉSUMÉ
Neurologic manifestations are an immediate consequence of SARS-CoV-2 infection, the etiologic agent of COVID-19, which, however, may also trigger long-term neurological effects. Notably, COVID-19 patients with neurological symptoms show elevated levels of biomarkers associated with brain injury, including Tau proteins linked to Alzheimer's pathology. Studies in brain organoids revealed that SARS-CoV-2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to the recruitment of Tau into stress granules (SGs) operated by the nucleocapsid protein (NCAP) of SARS-CoV-2. To test this hypothesis, we investigated whether NCAP interacts with Tau and localizes to SGs in hippocampal neurons in vitro and in vivo. Mechanistically, we tested whether SUMOylation, a posttranslational modification of NCAP and Tau, modulates their distribution in SGs and their pathological interaction. We found that NCAP and Tau colocalize and physically interact. We also found that NCAP induces hyperphosphorylation of Tau and causes cognitive impairment in mice infected with NCAP in their hippocampus. Finally, we found that SUMOylation modulates NCAP SG formation in vitro and cognitive performance in infected mice. Our data demonstrate that NCAP induces Tau pathological changes both in vitro and in vivo. Moreover, we demonstrate that SUMO2 ameliorates NCAP-induced Tau pathology, highlighting the importance of the SUMOylation pathway as a target of intervention against neurotoxic insults, such as Tau oligomers and viral infection.
Sujet(s)
COVID-19 , Protéines de la nucléocapside des coronavirus , Hippocampe , Neurones , SARS-CoV-2 , Sumoylation , Protéines tau , Protéines tau/métabolisme , Animaux , Souris , Humains , Hippocampe/métabolisme , Hippocampe/anatomopathologie , COVID-19/métabolisme , COVID-19/anatomopathologie , COVID-19/virologie , SARS-CoV-2/pathogénicité , SARS-CoV-2/métabolisme , Phosphorylation , Protéines de la nucléocapside des coronavirus/métabolisme , Neurones/métabolisme , Neurones/anatomopathologie , Neurones/virologie , Petites protéines modificatrices apparentées à l'ubiquitine/métabolisme , Granules de stress/métabolisme , Souris de lignée C57BL , Phosphoprotéines/métabolisme , Mâle , Protéines nucléocapside/métabolisme , Dysfonctionnement cognitif/métabolisme , Dysfonctionnement cognitif/anatomopathologie , Dysfonctionnement cognitif/virologieRÉSUMÉ
Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta (Aß) deposition in cerebrovasculature. It is prevalent with aging and Alzheimer's disease (AD), associated with intracerebral hemorrhage, and contributes to cognitive deficits. To better understand molecular mechanisms, CAA(+) and CAA(-) vessels were microdissected from paraffin-embedded autopsy temporal cortex of age-matched Control (n = 10), mild cognitive impairment (MCI; n = 4), and sporadic AD (n = 6) cases, followed by label-free quantitative mass spectrometry. 257 proteins were differentially abundant in CAA(+) vessels compared to neighboring CAA(-) vessels in MCI, and 289 in AD (p < 0.05, fold-change > 1.5). 84 proteins changed in the same direction in both groups, and many changed in the same direction among proteins significant in at least one group (p < 0.0001, R2 = 0.62). In CAA(+) vessels, proteins significantly increased in both AD and MCI were particularly associated with collagen-containing extracellular matrix, while proteins associated with ribonucleoprotein complex were significantly decreased in both AD and MCI. In neighboring CAA(-) vessels, 61 proteins were differentially abundant in MCI, and 112 in AD when compared to Control cases. Increased proteins in CAA(-) vessels were associated with extracellular matrix, external encapsulating structure, and collagen-containing extracellular matrix in MCI; collagen trimer in AD. Twenty two proteins were increased in CAA(-) vessels of both AD and MCI. Comparison of the CAA proteome with published amyloid-plaque proteomic datasets identified many proteins similarly enriched in CAA and plaques, as well as a protein subset hypothesized as preferentially enriched in CAA when compared to plaques. SEMA3G emerged as a CAA specific marker, validated immunohistochemically and with correlation to pathology levels (p < 0.0001; R2 = 0.90). Overall, the CAA(-) vessel proteomes indicated changes in vessel integrity in AD and MCI in the absence of Aß, and the CAA(+) vessel proteome was similar in MCI and AD, which was associated with vascular matrix reorganization, protein translation deficits, and blood brain barrier breakdown.