Plasma exchange: An effective method to eliminate neurotoxic lipophilic chemicals from blood

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The Alzheimer's Management by Albumin Replacement (AMBAR) trial demonstrated the clinical efficacy of plasma exchange (PE) with albumin replacement for slowing the progression of disease in patients with mild‐to‐moderate Alzheimer's disease (AD). ¹ , ² Although the main hypothesized mechanism in AMBAR was a decrease in neurotoxic amyloid beta (Aβ) amount, its quantification in the cerebrospinal fluid revealed no clear evidence in this regard, implying the presence of alternative mechanisms beyond Aβ binding. At present, the elimination of dysfunctional albumin, inflammatory mediators, neurotoxic autoantibodies, and other pro‐aging‐related proteins have been proposed as possible underlying mechanisms. ³ Importantly, PE can effectively remove persistent organic pollutants (POPs) that have recently emerged as a novel risk factor for dementia. ⁴ , ⁵

Human adipose tissue is contaminated by a large number of environmental pollutants, yet this is often ignored by researchers and clinicians. ⁶ The most problematic chemicals in terms of neurodegenerative disease risk would be POPs as many of them are well‐known neurotoxins. ⁴ As a typical example of lipopilic chemical mixtures, these compounds share characteristics such as high lipophilicity, resistance to biodegradation, bioaccumulation in the food chain, and long half‐life. ⁷ The general population in modern societies is living with a chronic exposure to low‐dose POPs. ⁷

The dynamics of POPs in adipose tissue can explain the puzzling relationships of obesity or weight loss with the dementia risk reported in previous human studies ⁴ , ⁵ because POPs are continuously released into circulation from adipose tissue through controlled or uncontrolled lipolysis. Individuals with increased lipolysis may be at a high risk of dementia as neurotoxic POPs in circulation can reach the brain more easily than ones in adipose tissue. These individuals are either obese having dysfunctional adipocytes or those who have experienced weight loss. Obesity and weight loss are two contrasting situations in terms of the amount of adipose tissue; however, both of them release POPs from adipose tissue into the circulation. The dynamics of POPs may be a missing link for many puzzling findings in the field of obesity which have not been explained to date. ⁶

Importantly, lipid apheresis (e.g., PE) is an effective method to directly eliminate POPs from blood as a result of the binding of POPs to various lipoproteins. ⁸ Gube et al. evaluated the efficacy of PE and double filtration plasmapheresis (DFPP) in eliminating polychlorinated biphenyls (PCBs, a typical class of POPs) from the blood of PCB workers in a capacitor recycling company in two phases. ⁹ In phase I, the levels of PCBs in blood were monitored after a single apheresis (PE or DFPP) for 2 weeks. In phase II, weekly DFPP apheresis was performed 12 times over a period of 3 months, and the changes in PCB levels were measured before and after each treatment, and 4 weeks after the last treatment. In phase I, both procedures yielded a reduction in PCB levels by approximately 50% after a single apheresis, yet the PCB levels quickly returned. Phase II also demonstrated significant reduction in the PCB levels during each apheresis treatment, which was followed by an increase in the PCB levels until the next round of apheresis. Although PCB levels in blood showed a decreasing pattern within the 12 apheresis treatments, the levels increased after treatment cessation.

Based on these observations, the authors concluded that lipid apheresis was not recommended to reduce the PCB body burden owing to this “rebounding phenomenon.” ⁹ Rebounding POPs in blood following apheresis is the result of a shift of POPs from adipose tissue to circulation as there is a steady‐state equilibrium of POPs between adipose tissue and serum. ¹⁰ However, it is reasonable to assume that participants in the AMBAR trial also experienced periodic decreases in POP levels in blood during the trial period. Despite the rebounding of POPs in blood, a decrease in POP levels may still contribute to the decrease in the absolute amount of POPs reaching the brain.

Another important clinical implication of lipid apheresis is the fact that unintentional weight loss is a significant predictor of poor prognosis in patients with dementia or mild cognitive impairment. ¹¹ Unintentional weight loss is currently regarded as a bystander effect related to disease progression rather than a risk factor. However, unintentional weight loss can directly affect the progression of dementia through the release of POPs from adipose tissue into the circulation. ⁴ Among these patients, elimination of POPs through lipid apheresis can be actively considered to reduce the amount of POPs reaching the brain. Even obese persons who have lost weight intentionally need to consider lipid apheresis to minimize possible long‐term cognitive damage due to the release of POPs. ⁵

CONFLICT OF INTEREST

The authors declare no conflicts of interest. Author disclosures are available in the supporting information.

Supporting information

Supporting Information