Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer’s continuum

Vilor‐Tejedor, Natàlia; Ciampa, Iacopo; Operto, Greg; Falcón, Carles; Suárez‐Calvet, Marc; Crous‐Bou, Marta; Shekari, Mahnaz; Arenaza‐Urquijo, Eider M.; Milà‐Alomà, Marta; Grau‐Rivera, Oriol; Minguillón, Carolina; Kollmorgen, Gwendlyn; Suridjan, Ivonne; Zetterberg, Henrik; Blennow, Kaj; Guigó, Roderic; Molinuevo, José Luís; Gispert, Juan Domingo

doi:10.1002/alz.051799

Cited by 12 publications

(17 citation statements)

References 31 publications

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“…40 Recent studies also reported that CSO-EPVS was associated with baseline tau deposition but not β-amyloid deposition in the brain in cognitively normal older adults 12 and in patients with AD continuum. 41 Furthermore, our subgroup analyses according to cognitive status demonstrated that CSO-EPVS was a predictor of longitudinal decline in the MMSE scores only in patients without dementia with AD continuum. Although insignificant results in patients with dementia with AD continuum might be due to the floor effect, 42 this result suggests that CSO-EPVS is an important imaging marker of future cognitive decline in the early stage of AD.…”

Section: Discussionmentioning

confidence: 73%

Association of Enlarged Perivascular Spaces With Amyloid Burden and Cognitive Decline in Alzheimer Disease Continuum

et al. 2022

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Background and Objectives:To investigate the effects of enlarged perivascular space (EPVS) on amyloid burden and cognitive function in Alzheimer’s disease (AD) continuum.Methods:We retrospectively reviewed 208 patients with AD across the cognitive continuum (preclinical, prodromal, and AD dementia) who showed amyloid deposition on 18F-florbetaben positron emission tomography scans and 82 healthy controls. EPVSs were counted for each patient in the basal ganglia (BG), centrum semiovale (CSO), and hippocampus (HP) on axial T2-weighted images. Patients were then classified according to the number of EPVS into the EPVS+ (> 10 EPVSs) and EPVS– (0–10 EPVSs) groups for the BG and CSO, respectively. In terms of HP-EPVS, equal or more than seven EPVSs on bilateral hemisphere were regarded as the presence of HP-EPVS. After adjusting for markers of small vessel disease (SVD), multiple linear regression analyses were performed to determine the inter-group differences in global and regional amyloid deposition and cognitive function at the time of diagnosis of AD continuum. A linear mixed model was used to assess the effects of EPVSs on the longitudinal changes in the Mini-Mental State Examination (MMSE) scores.Results:Amyloid burden at the time of diagnosis of AD continuum was not associated with the degree of BG-, CSO-, or HP-EPVS. BG-EPVS affected language and frontal/executive function via SVD markers and HP-EPVS was associated with general cognition via SVD markers. However, CSO-EPVS was not associated with baseline cognition. A higher number of CSO-EPVS was significantly associated with a more rapid decline in MMSE scores (β = −0.58, SE = 0.23, p = 0.011) independent of the amyloid burden. In terms of BG and HP, there was no difference between the EPVS+ and EPVS– groups in the rate of longitudinal decreases in MMSE scores.Discussion:Our findings suggest that BG-, CSO-, and HP-EPVS are not associated with baseline β-amyloid burden or cognitive function independently of SVD at the diagnosis of AD continuum. However, CSO-EPVS appears to be associated with the progression of cognitive decline in an amyloid-independent manner. Further studies are needed to investigate whether CSO-EPVS is a potential therapeutic target in patients with AD continuum.

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Section: Discussionmentioning

confidence: 73%

Association of Enlarged Perivascular Spaces With Amyloid Burden and Cognitive Decline in Alzheimer Disease Continuum

et al. 2022

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“…1,3,5,8,[15][16][17][18][19][20][21][22] Additionally, some studies have investigated the relation with inflammation markers, cerebral amyloid angiopathy, and CSF biomarkers. 6,23,24 Recent exploration into the genomics of PVS has also unveiled interesting insight into regional variabilities and genetic overlap with neurodegenerative diseases. 25,26 However, previous studies have utilized heterogeneous methods to assess PVS, combined with often small samples, resulting in conflicting findings that are difficult to interpret.…”

Section: Study Fundingmentioning

confidence: 99%

Determinants of Perivascular Spaces in the General Population

et al. 2023

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Background and Objectives:Perivascular spaces (PVS) are emerging markers of cerebral small vessel disease, but research on their determinants has been hampered by conflicting results from small single studies employing heterogeneous rating methods. In this study we therefore aimed to identify determinants of PVS burden in a pooled analysis of multiple cohort studies using one harmonized PVS rating method.Methods:Individuals from ten population-based cohort studies with adult participants from the UNIVRSE consortium and the UK Biobank were included. On magnetic resonance imaging scans, we counted PVS in four brain regions (mesencephalon, hippocampus, basal ganglia, and centrum semiovale) according to a uniform and validated rating protocol, both manually and automated using a deep learning algorithm. As potential determinants, we considered demographics, cardiovascular risk factors,APOEgenotypes, and other imaging markers of cerebral small vessel disease. Negative binomial regression models were used to examine the association between these determinants and PVS counts.Results:In total, 39,976 individuals were included (age range 20-96 years). The average count of PVS in the four regions increased from the age of 20 years (0-1 PVS) to 90 years (2-7 PVS). Men had more mesencephalic PVS (odds ratio [95% confidence interval] = 1.13 [1.08-1.18] compared to women), but less hippocampal PVS (0.82 [0.81-0.83]). Higher blood pressure, in particular diastolic pressure, was associated with more PVS in all regions (odds ratios between 1.04-1.05). Hippocampal PVS showed higher counts with higher HDL cholesterol levels (1.02 [1.01-1.02]), and glucose levels (1.02 [1.01-1.03]), as well asAPOEε4-alleles (1.02 [1.01-1.04]). Furthermore, white matter hyperintensity volume and presence of lacunes were associated with PVS in multiple regions, but most strongly with the basal ganglia (1.13 [1.12-1.14] and 1.10 [1.09-1.12], respectively).Discussion:Various factors are associated with the burden of PVS, in part regionally-specific, which points towards a multifactorial origin beyond what can be expected from PVS-related risk factor profiles. This study highlights the power of collaborative efforts in population neuroimaging research.

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“…Increased perivascular space is a phenotype frequently observed in patients with Alzheimer's diseases [32]. However, the underline cause for the "increased perivascular space" phenotype was not fully understood.…”

Section: Luminal and Vascular Build-up Of Ab Is Associated With Vascu...mentioning

confidence: 99%

Senile plaques in Alzheimer's disease arise from Aβ‐ and Cathepsin D‐enriched mixtures leaking out during intravascular haemolysis and microaneurysm rupture

et al. 2022

FEBS Letters

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Senile plaques are a pathological hallmark of Alzheimer's disease (AD), yet the mechanism underlying their generation remains unknown. Beta‐amyloid peptide (Aβ) is a major component of senile plaques. We analysed AD brain tissues with histochemistry, immunohistochemistry and fluorescence imaging to examine the neural, vascular or blood Aβ contribution to senile plaque development. We found little neural marker co‐expression with plaque Aβ, while co‐expression of blood markers, such as Haemin and ApoE, was abundant. The plaque cores were structured with vascular and glial proteins outside and blood metabolites inside, co‐localizing with a characteristic of Hoechst staining‐independent blue autofluorescence. Erythrocyte‐interacting Aβ is linked to coagulation, elevated calcium and blue autofluorescence, and it is associated with intravascular haemolysis, atherosclerosis, cerebral amyloid angiopathy, microaneurysm, and often with Cathepsin D co‐expression. We identified microaneurysms as major sites of amyloid formation. Our data suggest that senile plaques arise from Aβ‐ and Cathepsin D‐enriched mixtures leaking out during intravascular haemolysis and microaneurysm rupture.

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Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer’s continuum

Cited by 12 publications

References 31 publications

Association of Enlarged Perivascular Spaces With Amyloid Burden and Cognitive Decline in Alzheimer Disease Continuum

Association of Enlarged Perivascular Spaces With Amyloid Burden and Cognitive Decline in Alzheimer Disease Continuum

Determinants of Perivascular Spaces in the General Population

Senile plaques in Alzheimer's disease arise from Aβ‐ and Cathepsin D‐enriched mixtures leaking out during intravascular haemolysis and microaneurysm rupture

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