Ascorbic Acid and Rates of Cognitive Decline in Alzheimer’s Disease

 

Reference: Bowman GL, et al. Ascorbic Acid and Rates of Cognitive Decline in Alzheimer’s Disease. Journal of Alzheimer’s Disease 2009, Vol 16 pgs 93-98.

Commentary: by Kelly Green Jennings, ND, LAc, MSOM

Design: A controlled longitudinal biomarker study

Participants: 32 patients with mild to moderate Alzheimer’s Disease (AD)

Study Parameters: All 32 patients were assessed at baseline and 12 months for CSF and plasma ascorbic acid (AA) content as well as CSF: Albumin ratios. Clinical evaluation included medical history, physical exam, Mini-Mental Status Exam, Clinical Dementia Rating (CDR), Alzheimer’s Disease Assessment Scale-cognitive subscale, Haschinski ischemia score as a measure of vascular burden, and Geriatric Depression Scale. Lumbar CSF and peripheral blood were collected at baseline. Supplementation was assessed by interview with caregiver including examination of all containers from which subjects were regularly taking pills at baseline and 12 month visits.

Main Outcome Measure: The primary aim of this study was to determine whether brain ascorbic acid concentrations can predict cognitive decline in adults with mild to moderate AD. A secondary function was to study how these antioxidant concentrations in the CSF and plasma are modified by blood brain barrier disruption.

Background: The integrity of the blood brain barrier (BBB) is known to be essential for the health of the brain. This barrier acts as a sort of semi-permeable membrane, allowing for the passive transport of some molecules, the active transport of other molecules into the brain and the necessary discharge of certain end-product metabolites that are toxic to the brain. It also serves to maintain high concentration gradients of specific nutrients that would otherwise diffuse from the brain to peripheral tissues.

Antioxidants have been shown to reduce oxidative damage to neurons and reduce the amyloid plaque formation that is characteristic of AD. Ascorbic acid (AA:Vitamin C) is a potent water soluble antioxidant that is highly concentrated in the brain and the cerebrospinal fluid. Some investigators have called AA the “nourishing liquor” that constantly surrounds the brain. AA is not synthesized in the brain; rather it is actively transported across the basolateral membrane of the choroid plexus by a specific sodium dependent transporter into the epithelium and then released into the CSF. The maintenance of high CSF levels of AA relies on this active transport system and the barrier integrity of the BBB, keeping the CSF: plasma ratio of AA at about 3-4:1.

While a complete understanding of the etiology of AD remains obscure, the accumulation of oxidative damage in areas of the brain responsible for memory and higher cognitive faculties is a consistent finding. It has been theorized that the breakdown of the BBB may be implicated in this pathophysiology of AD. Barrier integrity of the blood-CSF barrier and choroid plexus can be measured using the CSF Albumin Index. Serum albumin levels are normally about 200 times higher than that found in the CSF. If there is BBB dysfunction or disruption, the CSF Albumin Index is increased due to albumin’s greater access to the CSF from the serum through the ‘leaky’ barrier.

Key Findings: In this study, 32 adults that were followed for one year with mild-to-moderate AD had statically significant rates of cognitive decline that could be correlated with CSF: plasma AA ratio (p=.03). The authors also found an inverse relationship between CSF: plasma AA ratio and the CSF Albumin Index.

Practical Implications: Tight junctions between endothelial cells maintain the BBB. An intact BBB restricts molecule transportation at the luminal (blood-facing) and abluminal (brain-facing) sides. This is largely mediated by the molecular weight and lipid solubility of a given molecule; with lipid soluble agents able to cross the BBB more readily than water-soluble agents. Selective pinocytosis and other transport molecules permit specific agents to cross an otherwise intact BBB, so that the BBB has both a barrier and carrier function. Specific transporters mediate an influx of substrates into the brain while other transport systems at the abluminal side of the BBB eliminate potentially toxic molecules like amyloid β(Aβ).

According to the neurovascular hypothesis of AD, which has been developed over the past decade, Aβ peptide clearance from the CNS across the BBB is disturbed by angiogenesis and cerebrovascular dysfunction. BBB changes are distributed in similar areas to the amyloid pathology seen in sporadic AD. Thus, the changes in the BBB may be the initiating event in the neurodegeneration of AD, or this impairment may simply be a marker of a brain damaged by amyloid deposition.

This may lend truth to the phrase “going soft in the brain”. It seems likely that the ability to maintain a high CSF: plasma AA ratio would be a marker of a healthier brain, one with an intact BBB that is more able to cope with the neurodegenerative processes of AD. However, it has been observed that CSF: plasma AA ratios have actually been found to be higher in patients with Alzheimer’s disease than in controls. It is theorized that these higher ratios are a reflection of an “increased consumption” of AA by an oxidatively stressed brain.

Based on this evidence, it would seem to follow that AD patients with higher CSF: plasma AA ratios would have more rapid rates of decline. The opposite is actually found to be true in this study. The slowest rates of cognitive decline were seen in those patients who had the highest CSF: plasma AA ratio. This evidence seems to support the theory that BBB integrity plays a crucial role in AD progression.

This is the first prospective study of cognitive decline of AD that quantifies CSF and plasma AA content and BBB integrity as modifiers of disease progression. Its strengths lie in its prospective design, consensus diagnosis of mild-to-moderate AD, and the simultaneous collection of CSF and plasma AA and serum albumin. The study is limited by its small sample size (n=32) and that CSF and plasma AA were only measured at two points; baseline and 12 months.

The study does however raise the possibility that BBB dysfunction accelerates the rate of degeneration of AD by impairing the ability of the brain to concentrate AA and potentially other neuroprotective nutrients. While it is certain that there is much more involved in the etiology and cognitive decline of AD than the brain’s ability to concentrate AA; this study does offer some novel ways to think of the neurodegenerative processes of AD. Clinical application remains to be seen.

About Kelly Jennings, ND
Kelly Jennings, ND, is a board certified naturopathic physician and licensed acupuncturist. She graduated valedictorian of her class at the National College of Natural Medicine in 2007. She also has a B.A. with Honors in Neuroscience from Amherst College in Massachusetts and was clinical research associate at Memorial Sloan Kettering Cancer Center in New York City prior to medical school. She is co-author of The Breast Cancer Companion, has been published in several medical journals and is writing a seasonal dietary therapy manual for patients. She is currently in practice at Urban Wellness Group in Portland, Oregon.

Copyright © 2009 by the Natural Medicine Journal All rights reserved. No part of this article may be reproduced in any form without the written permission of the publisher.