Cerebral amyloid angiopathy is associated with glymphatic transport reduction and time-delayed solute drainage along the neck arteries

Chen, Xinan; Liu, Xiaodan; Koundal, Sunil; Elkin, Rena; Zhu, Xiaoyue; Monte, Brittany; Xu, Feng; Dai, Feng; Pedram, Maysam; Lee, Hedok; Kipnis, Jonathan; Tannenbaum, Allen; Nostrand, William E. Van; Benveniste, Helene

doi:10.1038/s43587-022-00181-4

Cited by 43 publications

(33 citation statements)

References 54 publications

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“…In our study, a lower ALPS index was proved to be associated with CSVD markers in patients. Our results may indicate glymphatic dysfunction in CAA, with consistent trends on disease severity, which is in line with previous studies [34, 35]. The vasomotion resulting from contractibility of vascular smooth muscle cells may influence glymphatic drainage [36].…”

Section: Discussionsupporting

confidence: 92%

Glymphatic dysfunction correlates with severity of small vessel disease and cognitive impairment in cerebral amyloid angiopathy

et al. 2022

Euro J of Neurology

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Background and purpose: Cerebral amyloid angiopathy (CAA) is characterized by β-amyloid deposition in cortical and leptomeningeal arterioles, which might result from glymphatic dysfunction. The aim was to explore glymphatic function in CAA using the non-invasive diffusion tensor image analysis along the perivascular space method.Methods: Sixty-three patients with CAA were prospectively recruited together with seventy age-and sex-matched normal controls. The Mini-Mental State Examination and Montreal Cognitive Assessment were applied to screen global cognitive status. Magnetic resonance imaging scans were conducted to calculate the index for diffusivity along the perivascular space (ALPS index), and linear regression models were used to assess its relationships with cerebral small vessel disease (CSVD) markers, cognitive status and blood biomarkers. Cox proportional hazard models were applied to explore the role of the baseline ALPS index in disease recurrence. Results:Patients with CAA exhibited a lower ALPS index than controls globally (p < 0.001).In addition, a lower ALPS index was related to more enlarged perivascular space in basal ganglia (p = 0.026), more lacunes (p < 0.001), higher white matter hyperintensity Fazekas score (p = 0.049), elevated total magnetic resonance imaging burden of CSVD (p = 0.034) and lower Mini-Mental State Examination (p = 0.001) as well as Montreal Cognitive Assessment (p < 0.001) in CAA. During a median follow-up of 4.1 years, a higher ALPS index was associated with lower disease recurrence (p = 0.022). The ALPS index was also negatively correlated with serum soluble intercellular adhesion molecule-1, neurofilament light and chitinase-3-like protein 1 in CAA. Conclusions: Patients with CAA showed impaired glymphatic function. The ALPS index was significantly related to CSVD severity, cognitive impairment and disease recurrence in CAA.

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Section: Discussionsupporting

confidence: 92%

Glymphatic dysfunction correlates with severity of small vessel disease and cognitive impairment in cerebral amyloid angiopathy

et al. 2022

Euro J of Neurology

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“…FMNL2 -mediated enlargement of perivascular space can serve to facilitate both glympathic and blood–brain barrier clearance mechanisms. Recent findings confirm our hypothesis that perivascular remodeling is a critical response to amyloid pathology [ 21 , 46 ] and could act as the interface between CVRFs and AD. A recent single cell transcriptomics analyses also confirmed our findings that FMNL2 is upregulated in astroglial cell populations in human AD brains [ 37 ].…”

Section: Discussionsupporting

confidence: 87%

FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer’s disease

et al. 2022

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Alzheimer’s disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle age and later and is frequently accompanied by cerebrovascular pathology at death. An interaction between CVRFs and genetic variants might explain the pathogenesis. Genome-wide, gene by CVRF interaction analyses for AD, in 6568 patients and 8101 controls identified FMNL2 (p = 6.6 × 10–7). A significant increase in FMNL2 expression was observed in the brains of patients with brain infarcts and AD pathology and was associated with amyloid and phosphorylated tau deposition. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology. Amyloid toxicity in zebrafish increased fmnl2a expression in astroglia with detachment of astroglial end feet from blood vessels. Knockdown of fmnl2a prevented gliovascular remodeling, reduced microglial activity and enhanced amyloidosis. APP/PS1dE9 AD mice also displayed increased Fmnl2 expression and reduced the gliovascular contacts independent of the gliotic response. Based on this work, we propose that FMNL2 regulates pathology-dependent plasticity of the blood–brain-barrier by controlling gliovascular interactions and stimulating the clearance of extracellular aggregates. Therefore, in AD cerebrovascular risk factors promote cerebrovascular pathology which in turn, interacts with FMNL2 altering the normal astroglial-vascular mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain.

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“…Moreover, CAA of meningeal vessels in Alzheimer’s disease occurs earlier than in intracerebral vessels. 8,65,66 Similar pathology in meninges is demonstrated in 5xFAD mice, and aggravated by ablation of meningeal lymphatics suggesting a contribution to amyloid clerance. 53 In our work, amyloid was probed with 4G8, which displays broad reactivity to amyloid species.…”

Section: Discussionmentioning

confidence: 67%

Characterization of non-human primate dura in health and neurodegeneration

Romanova

Janson

Müller

et al. 2022

Preprint

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Brain meninges and associated vasculature participate in brain clearance and are implicated in many neurological conditions such as Alzheimers disease, meningitis, multiple sclerosis, stroke, and traumatic brain injury. However, most of our knowledge concerning brain clearance via meninges is based on rodent data, and relevance to human disease remains unclear. One of the technical barriers in studies of meningeal physiology in health and disease is that existing imaging modalities are suboptimal for large and optically non-transparent meningeal tissue of humans and non-human primate (NHP) animal models. To address this barrier, we performed first characterization of NHP dura by high resolution confocal microscopy of clarified tissue. We investigated vascular structures and resident cells in normal monkeys and primate models of tauopathy and synucleinopathy. We demonstrated the presence of an extensive meningeal vascular network covering the entire tissue surface with resolution to the smallest capillaries. This is also the first work to map lymphatic vessels in the dura of non-human primate (NHP). Overall, the NHP lymphatic meningeal system resembles the anatomy found in rat dura, but it is more complex. Analysis of dura from NPH models of tauopathy and synucleinopathy revealed an association with disease-specific biomarkers (amyloid, tau, alpha-synuclein) with both the blood and lymphatic vasculature. This work has broad relevance to many brain diseases where solute accumulation and abnormal macromolecular clearance is a part of the pathogenesis.

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Cerebral amyloid angiopathy is associated with glymphatic transport reduction and time-delayed solute drainage along the neck arteries

Cited by 43 publications

References 54 publications

Glymphatic dysfunction correlates with severity of small vessel disease and cognitive impairment in cerebral amyloid angiopathy

Glymphatic dysfunction correlates with severity of small vessel disease and cognitive impairment in cerebral amyloid angiopathy

FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer’s disease

Characterization of non-human primate dura in health and neurodegeneration

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