Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA), updates in 2022-2023. Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease: Opportunities for therapy

Abstract

This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal Fluid (CLIC) group, within the Vascular Professional Interest Area (PIA) of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). The overarching objectives of the CLIC group are to: (1) understand the age-related physiology changes that underlie impaired clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) (CLIC); (2) understand the cellular and molecular mechanisms underlying intramural periarterial drainage (IPAD) in the brain; (3) establish novel diagnostic tests for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), retinal amyloid vasculopathy, amyloid-related imaging abnormalities (ARIA) of spontaneous and iatrogenic CAA-related inflammation (CAA-ri), and vasomotion; and (4) establish novel therapies that facilitate IPAD to eliminate amyloid β (Aβ) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy.

Keywords: ARIA; IPAD; ISTAART; amyloid; cerebrospinal fluid; clearance; interstitial fluid.

FIGURE 1

The possible mechanism by which immune complexes disrupt IPAD. In (A), antigens (peptides) in the extracellular space interact with IgG extravasated from the circulation resulting in immune complex formation and fixation of complement C3. The immune complexes formed block the arterial basement membranes that represent the IPAD pathway. In (B), the drainage of peptides such as Aβ is blocked by the presence of immune complexes or pre‐existing CAA in the arterial basement membranes

FIGURE 2

Diagram to illustrate the drainage pathways for CSF and interstitial fluid (ISF) to cervical lymph nodes. Reproduced with permission. CSF and ISF drain to lymph nodes by different and distinct pathways. In humans, CSF drains into the blood of venous sinuses through well‐developed arachnoid villi and granulations (AG). Lymphatic drainage of CSF occurs via nasal and dural lymphatics and along cranial and spinal nerve roots (outlined in green). Channels that pass from the subarachnoid space through the cribriform plate allow passage of CSF (green line), T cells and antigen presenting cells (APC) into nasal lymphatics (NL) and cervical lymph nodes (CLN). CSF from the lumbar subarachnoid space drains to lumbar lymph nodes. ISF from the brain parenchyma drains along basement membranes in the walls of cerebral capillaries and arteries (blue arrows) to cervical lymph nodes adjacent to the internal carotid artery just below the base of the skull. This narrow intramural perivascular drainage pathway does not allow the traffic of APC. There is interchange between CSF and ISF (convective influx/glymphatic system) as CSF enters the surface of the brain alongside penetrating arteries

FIGURE 3

The PET tracer [11C]‐Butanol was used as a biomarker for CSF clearance. The data show in elderly individuals with brain amyloid deposits ([11C]‐PiB imaging) that compared with controls, nasal turbinate tracer drainage is slower. These data suggest that the slowed ventricular CSF drainage found in neurodegenerative diseases such as Alzheimer's can be detected peripherally