A binary detector of preclinical and clinical stages of Alzheimer's disease

Magnetoencephalography (MEG) spatio-temporal localization of prefrontal sensory gating generator activations to simple tones is shown to have high potential as a discrete non-invasive biomarker of Alzheimer's disease (AD) at the individual level during both preclinical and clinical stages. The proposed biomarker shows a large effect size (0.9) and high accuracy, sensitivity and specificity (100%) in identifying symptomatic AD patients within a research sample, according to Sanja Josef Golubić Ph.D., a physicist at the University of Zagreb and leading author of a new study published in the neuroimaging journal Human Brain Mapping.

"Ultraweak neuromagnetic fields were acquired with a 275-high-order gradiometer, whole-head MEG system inside a two-layer magnetically shielded room, while anatomical data were obtained from T1-weighted and T-2 weighted turbo spin echo magnetic resonance images from a 1.5-T MR scanner at the Mind Research Network in Albuquerque, New Mexico. To localize cortical sources of the extracranially measured fields evoked by an auditory oddball paradigm, we modeled neural generators assuming multiple current dipoles embedded in a spherical volume conductor. We conducted spatio-temporal source localization during entire 100 ms post-stimulus time window. Estimation of the time invariant parameters (spatial locations) was derived using nonlinear minimization and kept constant for the selected time window, while a linear estimation of the associated time varying parameters (source strengths and orientation) were calculated for each time instance," explains Josef Golubić.

The medial prefrontal cortex and the bilateral supratemporal areas were identified as cortical regions where the gating network was localized. The three gating generator topologies were identified across subjects and two conditions, based on the activation of a medial prefrontal generator.

"The symptomatic AD patients were lacking any medial prefrontal gating generator activations to either the deviant or standard tones of a paradigm. By contrast, high functional controls activated the prefrontal generator in response to both paradigm tones. We also detected a sub-group of controls characterized by the absence of prefrontal gating generator activation for the standard tone only and significantly lower scores at the Mini Mental Status Exam and delayed Rey-Osterreith Complex Figure Test. We speculate that these individuals may be in a possible preclinical AD phase since they show both neuropsychological and neurophysiological impairments characteristic for an AD type of dementia, although they did not yet meet clinical criteria for the early stage of symptomatic AD," says Josef Golubić, who together with Cheryl Aine, Julia Stephen, John Adair, Janice Knoefel and Selma Supek as senior author, form the research team.

"Our non-invasive AD biomarker does not require estimation of cut-off levels or standardization processes, which is the main problem with proposed AD markers. Its strength lies in the simplicity of using a binary value i.e. activated or not-activated prefrontal sensory gating generator. The low sensitivity to individual heterogeneity and variability due to the binary nature of impaired medial prefrontal generator activation is probably the most important property of the proposed biomarker," says Josef Golubić.

The research team reports that localization of a discrete prefrontal gating activation is a highly promising AD marker at the individual level, but this approach needs to be further tested in a large independent sample and requires assessment in longitudinal clinical studies.

More information:
"MEG biomarker of Alzheimer's disease: Absence of a prefrontal generator during auditory sensory gating ", Sanja Josef Golubic, Cheryl J Aine, Julia M Stephen, John C Adair, Janice E Knoefel, Selma Supek. Human Brain Mapping, 10.1002/hbm.23724. onlinelibrary.wiley.com/doi/10 … 2/hbm.23724/abstract

Provided by University of Zagreb