Preclinical AD: New Findings Indicate Biphasic Trajectory for Brain Structural Changes
New findings published in Alzheimer’s & Dementia have confirmed a biphasic trajectory for brain structural changes during preclinical Alzheimer disease (AD), which investigators say may “have direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials.”
In their study, the investigators observed increased cortical thickness and decreased cortical diffusivity between 15 and 20 years prior to the estimated onset of symptoms. This was followed by cortical thinning and increases in cortical diffusivity, which occurred in later preclinical and symptomatic stages of AD. The investigators noted that the inflection points 16 to 19 years prior to the estimated onset of symptoms coincide with the start of tau biomarker changes.
Neurology Learning Network discussed the study and its implications further with first author Victor Montal, PhD(c), MSc, with the Memory Unit and Neurology Department at Hospital de la Santa Creu i Sant Pau, and the Center of Biomedical Investigation Network for Neurodegenerative Diseases in Spain.
Neurology Learning Network: Could you discuss your biphasic model for brain structural changes in preclinical AD, as well as its significance?
Victor Montal: The biphasic model is based on a decade-long research effort in sporadic AD and autosomal dominant AD (ADAD). In a paper published in 2010, which included a small cohort of participants with ADAD—the PICOGEN project—we realized that individuals at early stages of the disease (as long as 20 years prior to symptoms onset) showed an unexpected pattern of increased cortical thickness, compared with family members who did not harbor the mutation. We hypothesized those increases in cortical thickness were amyloid-related, probably caused by an inflammatory process that could result in glia recruitment and activation and/or neuronal hypertrophy.
We further investigated this hypothesis in a cohort of cognitively healthy elderly participants in the preclinical AD spectrum, in whom we found a direct relationship between more amyloidosis and increased cortical thickness, in the absence of abnormal cerebrospinal fluid (CSF) p-tau levels. However, when both CSF amyloid and tau biomarkers were abnormal, we found more atrophy. In a follow-up longitudinal study in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we showed that indeed amyloidosis in the absence of tau (Sperling preclinical stage 1) was associated with attenuated rates of atrophy, whereas when both biomarkers were abnormal (Sperling preclinical stage 2), there was a shift towards accelerated atrophy.
To further investigate these changes, we developed a novel measure to quantify the cortical microstructural changes based on diffusion weighted imaging and specifically based on the metric mean diffusivity. Our rationale was that, under an amyloid-related inflammatory state, water diffusivity in the cortex would be restricted due to the increased barriers associated with the larger intracellular compartment associated with neuroinflammation in the cortex (the intracellular water has restricted diffusivity due to the membranes and organelles). Indeed, we found that in this stage, the amyloid-positive but tau-negative subgroup had lower diffusivity in the cortex compared with participants with normal biomarker levels.
Nevertheless, we still needed to validate that the increases in cortical thickness and decreases in cortical diffusivity were directly related to neuroinflammation. In a recent work published this year in collaboration with the Karolinska Institute in Sweden, we showed in a cohort of participants with ADAD that increased levels of reactive astrocytes (measured using deprenyl positron emission tomography) were related to increased cortical thickness and decreased diffusivity in early stages of the preclinical phase.
Our latest manuscript, in which we used the biggest sample of participants with ADAD—the Dominantly Inherited Alzheimer’s Network cohort—we mathematically proved a biphasic trajectory in which cortical thickness is increased and cortical diffusivity is decreased around 20 years prior to symptom onset. We found an inflection point, changing the trajectories when the levels of phosphorylated tau, measured in the CSF, became abnormal. This inflexion point occurred 17 years prior to symptom onset.
Our findings have a strong impact in the disease models, especially in the early stages. Until recently, the accepted paradigm in the field was that cortical alterations followed a monotonic trajectory (i.e., cortical thickness did not sustain any alteration until 5 to 7 years before symptom onset). However, we expand the potential of magnetic resonance imaging (MRI) to detect AD-associated changes if we model nonlinear trajectories and interactions between biomarkers in a biphasic model.
NLN: You and your colleagues confirmed a biphasic trajectory for brain structural changes, with direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials. Could you discuss this in more detail?
Victor Montal: Our model might help to interpret results in antiamyloid and anti-inflammatory trials, which found paradoxal increased atrophy rates in the active arm of antiamyloid therapies. Atrophy is usually understood as synonymous with neurodegeneration. We propose that these increased atrophy rates in the active arm that successfully remove amyloid are not deleterious, in agreement with the decrease in tau biomarkers, and that this increased atrophy is not associated with cognitive decline. With the advent of novel and promising AD drugs, it is important to have good modeling of imaging biomarkers in order to correctly interpret the outcomes of the trials, even more so now that AD trials are moving to earlier stages and even primary and secondary prevention.
NLN: What areas of future research are still needed in this area?
Victor Montal: An important line of future research is to develop biomarkers to track neuroinflammation in preclinical AD. Most biomarkers, both in CSF (i.e., YKL40) or PET (i.e., microglia PET), track late stages of disease neuroinflammation. There is a need to develop novel and less expensive markers that can provide early-stage neuroinflammation information similar to the inflammation associated with deprenyl-PET uptake.
One potential candidate is the measurement of metabolite levels, such as myo-inositol and N-acetyl-aspartat, and their displacement proprieties using magnetic imaging spectroscopy. The development of such measures will help to study the pathophysiological alterations related to cortical thickness increases and cortical diffusivity decreases.
Another area of future research is the development of a signature (both in preclinical and prodomal AD) of cortical diffusivity alterations that would allow quantification of the microstructural changes in a single-scalar number. These quantifications might be essential in order to translate our model to direct application in clinical trials.
NLN: What key takeaways about this topic do you hope to leave with neurologists and neurology providers?
Victor Montal: The key message we would like to share is that cortical alterations in the continuum of AD follow a biphasic trajectory, and that interactions between biomarkers must be considered. This trajectory has implications on current AD models and the use of MRI as a surrogate marker of efficacy in clinical trials.
Montal V, Vilaplana E, Pegueroles J, et al. Biphasic cortical macro‐ and microstructural changes in autosomal dominant Alzheimer's disease. Alzheimers Dement. Published online November 16, 2020. doi:10.1002/alz.12224