The value of PSMD is that it provides an overall measurement and can detect abnormalities that are not yet visible as clearly defined lesions on structural MRI
Alejandra Morcillo-Nieto
Until now, PSMD had been studied in several diseases associated with white matter damage and cerebral small vessel disease, including cerebral amyloid angiopathy, but it had not been extensively applied to people with Down syndrome. “This metric had not been studied in Down syndrome. We therefore wanted to compare it with sporadic Alzheimer’s disease to determine whether our observations in this population followed a similar pattern and could help us understand shared disease mechanisms,” says Dr. Alejandra Morcillo-Nieto, first author of the study and a researcher with the Neuroimaging of Aging and Neurodegenerative Diseases research group at IR Sant Pau.
PSMD is obtained from diffusion imaging, a type of magnetic resonance imaging that analyzes the movement of water molecules in brain tissue. In healthy white matter, this movement is influenced by the organization of axons and myelin. When axonal damage, myelin loss, or microvascular abnormalities occur, diffusion becomes more heterogeneous.
“PSMD focuses on white matter tracts and provides an overall value for each individual. This makes it relatively easy to calculate and potentially useful as a complementary tool in research, clinical practice, and clinical trials,” Dr. Morcillo-Nieto explains. Unlike other diffusion metrics more commonly used in group analyses, PSMD provides an overall measurement for each individual, which may facilitate its interpretation and its potential incorporation as a complementary marker in clinical studies.
One of the main advantages of this measurement is its ability to detect microstructural abnormalities before the damage becomes visible using conventional MRI techniques. In the study, particularly among people with Down syndrome, PSMD identified abnormalities in cases where white matter hyperintensities were not yet present. These are MRI-visible lesions typically associated with vascular damage and loss of brain tissue integrity. “Diffusion imaging is inherently more sensitive to subtle changes than other conventional sequences. The value of PSMD is that it provides an overall measurement and can detect abnormalities that are not yet visible as clearly defined lesions on structural MRI,” the researcher adds.
The study indicates that PSMD increases with age across all the groups studied, but the increase is particularly pronounced among people with Down syndrome. In this population, differences compared with the control group began to emerge at around age 38, approximately 15 years before Alzheimer’s dementia typically becomes clinically apparent. “This is a relevant finding, but it must be interpreted with caution. The study does not yet follow the same individuals over time. Instead, it compares participants of different ages within a population in which the natural history of Alzheimer’s disease is very well characterized. The next step will be to confirm these findings through longitudinal studies,” Morcillo-Nieto says.
PSMD was also higher among individuals who already had symptoms of Alzheimer’s disease, both in the general population and among people with Down syndrome. However, once symptoms had appeared, the metric could not clearly distinguish between the prodromal and dementia stages. Higher PSMD values were also associated with poorer overall cognitive performance, both among people with sporadic Alzheimer’s disease and those with Down syndrome. In the latter group, the researchers used neuropsychological tests adapted to the characteristics of this population, allowing them to link white matter abnormalities to cognitive functioning in both clinical contexts.
“We observed a substantial increase when individuals progressed from an asymptomatic to a symptomatic stage. After that point, although PSMD may continue to increase, it does not appear to be as precise a tool for classifying disease severity. It may therefore be more useful as an early biomarker than as a staging marker,” Morcillo-Nieto summarizes.
The study also analyzed the relationship between PSMD and several cerebrospinal fluid biomarkers. The marker showing the most consistent association was neurofilament light chain (NfL), a protein released when axonal damage occurs. This relationship supports the idea that PSMD captures relevant structural abnormalities in white matter tracts, which are primarily composed of myelinated axons.
PSMD was also associated with established Alzheimer’s disease biomarkers, including beta-amyloid and tau, as well as markers of glial activation and inflammation. In the case of tau, the researchers observed an apparently unexpected result in sporadic Alzheimer’s disease: the association with pTau181 did not increase in parallel with PSMD but was instead inverse. According to the authors, one possible explanation is that this biomarker may reach a plateau and decline during more advanced stages, when neuronal loss reduces the amount of tissue capable of releasing it into the cerebrospinal fluid.
PSMD was also associated with cerebral microbleeds and white matter hyperintensities, two radiological markers linked to vascular damage and cerebral small vessel disease. Taken together, these findings suggest that white matter damage in Alzheimer’s disease does not depend on a single mechanism but instead results from a combination of neurodegenerative, vascular, and inflammatory processes.