The well understood pathways by which cerebrospinal fluid drains from the brain are the glymphatic system and cribriform plate. These paths become less functional with age, for different reasons, and the consequently reduced drainage of cerebrospinal fluid allows metabolic waste to build up in the brain. This includes the misfolded and normally folded but excess amyloid-β that is associated with the development of Alzheimer's disease. Researchers here show that clearing amyloid-β from the brain via immunotherapy does not improve glymphatic fluid flow over the course of the first few months following treatment, reinforcing a view of Alzheimer's and other neurodegenerative conditions in which glymphatic dysfunction is a contributing factor to the development of the disease rather than a consequence of the disease.
Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid-β peptides in the brain parenchyma, and impairment of interstitial waste clearance via the glymphatic system is suggested as one contributing factor. Recently approved disease-modifying monoclonal antibodies, such as lecanemab, are expected to slow cognitive decline by improving amyloid-β clearance. Diffusion tensor imaging along the perivascular space (DTIALPS) index has emerged as a noninvasive surrogate marker suggested to be associated with glymphatic activity. This index declines with normal aging and is significantly lower in patients with AD than in cognitively normal individuals.
The 13 participants included in this study were: (i) diagnosed with AD by neurologists; (ii) underwent brain magnetic resonance imaging (MRI) and subsequently initiated lecanemab therapy. Only participants who provided written informed consent were included. Mean DTI-ALPS index was 1.515 ± 0.152 at baseline and 1.513 ± 0.161 at 3 months, no significant difference.
The absence of early DTI-ALPS index improvement suggests that even though lecanemab treatment reduces plaque burden, the diffusion properties of perivascular spaces measured by DTI-ALPS do not change in the short term. DMT can reduce plaque burden and slow further cognitive worsening but does not restore lost function, likely reflecting the fact that neuronal damage and clearance system deficits have already been well established. Such observations, therefore, may reflect a multifactorial disease process that is not rapidly reversible during symptomatic stages, resulting in an unchanged early DTI-ALPS index.
Link: https://doi.org/10.1002/jmri.70118
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