The association of enlarged perivascular space with microglia-related inflammation and Alzheimer's pathology in cognitively normal elderly

Zeng, Qingze; Li, Kaicheng; Luo, Xiao; Wang, Shuyue; Xu, Xiaopei; Jiaerken, Yeerfan; Liu, Xiaocao; Hong, Luwei; Hong, Hui; Li, Zheyu; Fu, Yanv; Zhang, Tianyi; Chen, Yanxing; Liu, Zhongfan; Huang, Peiyu; Zhang, Minming

doi:10.1016/j.nbd.2022.105755

Cited by 27 publications

(29 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PVS dynamics are thus at the crossroads of hypertension, inflammation, and AD pathology and we here propose the notion that subjects along the AD continuum might face two related pathological processes that contribute to PVS enlargement (Figure 5). The first one could be a vicious cycle arising from Aβ and tau accumulation, which would hinder glymphatic clearance (13)(14)(15)19) Taking into account previous findings (24,26,27,29), we consider conceivable that neuroinflammation might be indeed triggered in response to, prior, and during, accumulation of neurotoxic waste as well as the formation of amyloid plaques (dashed lines in Figure 5), despite our results only partly supporting this hypothesis. However, limited availability of CSF AD biomarkers and IL-6 reduced the power for this analysis considerably.…”

Section: Pvs Pro Ression: Influence Of Inflammation Beyond Alzheimer'...supporting

confidence: 46%

Section: Introductionmentioning

confidence: 75%

“…The finding suggests that tau-induced neuroinflammation might impair clearance, which could lead to a vicious circle presumably comprising blood-brain-barrier permeability alterations and leakage of peripheral immune cells, further promoting neuroinflammation or neurotoxic waste into the PVS. Markers of cerebral small vessel disease (CSVD) (25) and neuroinflammation (26)-which are found consistently associated with the presence of enlarged PVS (24,27)-are also increasingly discussed as a potential aggravating factor in AD pathology (28,29). Taken together this suggests that PVS alterations could potentially link CSVD, neuroinflammation and AD pathology.…”

Section: Introductionmentioning

confidence: 99%

“…In line with the clearance hypothesis, PVS burden has been found to be associated with elevated levels of Aβ and tau(16,17), vascular Aβ deposition in cerebral amyloid angiopathy (CAA)(18–20), as well as with clinical diagnosis of mild cognitive impairment (MCI)(21) and AD(22,23). Moreover, a recent study revealed that microglial activation mediates the association between tau and PVS burden in the centrum semiovale (CSO)(24). The finding suggests that tau-induced neuroinflammation might impair clearance, which could lead to a vicious circle presumably comprising blood-brain-barrier permeability alterations and leakage of peripheral immune cells, further promoting neuroinflammation or neurotoxic waste into the PVS.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Perivascular space enlargement accelerates with hypertension, white matter hyperintensities, chronic inflammation, and Alzheimer’s disease pathology: evidence from a three-year longitudinal multicentre study

Menze,

Bernal,

Kaya

et al. 2023

Preprint

View full text Add to dashboard Cite

BackgroundPerivascular space (PVS) enlargement in ageing and Alzheimer’s disease (AD) and its exacerbators require further investigation.MethodsWe studied centrum semiovale (CSO) and basal ganglia (BG) PVS computationally over three to four annual visits in 557 participants of the DZNE multicentre DELCODE cohort. We tested volumetric changes of PVS in relation to ageing, sex, years of education, hypertension, AD diagnosis, and cerebrospinal-fluid-derived Amyloid and Tau positivity and interleukin 6 (IL-6).ResultsPVS volumes increased over time. PVS enlargement was associated with baseline white matter hyperintensities. BG-PVS enlargement was related to age and was faster with hypertension. CSO-PVS volumes increased faster with Amyloid and Tau positivity. Higher CSF IL-6 levels predicted PVS volume expansion in both regions and were associated with accelerated PVS enlargement in individuals with Amyloid and Tau positivity.ConclusionOur work supports the region-specific involvement of white matter hyperintensities, neurotoxic waste accumulation, and inflammation in PVS enlargement.

show abstract

Section: Pvs Pro Ression: Influence Of Inflammation Beyond Alzheimer'...supporting

confidence: 46%

Section: Introductionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Perivascular space enlargement accelerates with hypertension, white matter hyperintensities, chronic inflammation, and Alzheimer’s disease pathology: evidence from a three-year longitudinal multicentre study

Menze,

Bernal,

Kaya

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Both studies also support Iliff et al (2014) , who determined that following traumatic brain injury, mice lacking the AQP4 channel showed an increase in NFT pathology and neurodegeneration ( Iliff et al, 2014 ). A more recent study in normal patients with AD pathological biomarkers utilized an ePVS visual rating score to suggest that impairment in glymphatic clearance could contribute to tau accumulation through microglia neuroinflammation processes ( Zeng et al, 2022 ).…”

Section: Perivascular Spaces As a Biomarker For Alzheimer’s Diseasementioning

confidence: 99%

Perivascular spaces as a potential biomarker of Alzheimer’s disease

et al. 2022

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a highly damaging disease that affects one’s cognition and memory and presents an increasing societal and economic burden globally. Considerable research has gone into understanding AD; however, there is still a lack of effective biomarkers that aid in early diagnosis and intervention. The recent discovery of the glymphatic system and associated Perivascular Spaces (PVS) has led to the theory that enlarged PVS (ePVS) may be an indicator of AD progression and act as an early diagnostic marker. Visible on Magnetic Resonance Imaging (MRI), PVS appear to enlarge when known biomarkers of AD, amyloid-β and tau, accumulate. The central goal of ePVS and AD research is to determine when ePVS occurs in AD progression and if ePVS are causal or epiphenomena. Furthermore, if ePVS are indeed causative, interventions promoting glymphatic clearance are an attractive target for research. However, it is necessary first to ascertain where on the pathological progression of AD ePVS occurs. This review aims to examine the knowledge gap that exists in understanding the contribution of ePVS to AD. It is essential to understand whether ePVS in the brain correlate with increased regional tau distribution and global or regional Amyloid-β distribution and to determine if these spaces increase proportionally over time as individuals experience neurodegeneration. This review demonstrates that ePVS are associated with reduced glymphatic clearance and that this reduced clearance is associated with an increase in amyloid-β. However, it is not yet understood if ePVS are the outcome or driver of protein accumulation. Further, it is not yet clear if ePVS volume and number change longitudinally. Ultimately, it is vital to determine early diagnostic criteria and early interventions for AD to ease the burden it presents to the world; ePVS may be able to fulfill this role and therefore merit further research.

show abstract

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

Veitch,

Weiner,

Miller

et al. 2023

Alzheimer's & Dementia

View full text Add to dashboard Cite

The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co‐pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI‐4 aims to address by enrolling a diverse cohort.

show abstract

The association of enlarged perivascular space with microglia-related inflammation and Alzheimer's pathology in cognitively normal elderly

Cited by 27 publications

References 51 publications

Perivascular space enlargement accelerates with hypertension, white matter hyperintensities, chronic inflammation, and Alzheimer’s disease pathology: evidence from a three-year longitudinal multicentre study

Perivascular space enlargement accelerates with hypertension, white matter hyperintensities, chronic inflammation, and Alzheimer’s disease pathology: evidence from a three-year longitudinal multicentre study

Perivascular spaces as a potential biomarker of Alzheimer’s disease

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

Contact Info

Product

Resources

About