'Ideal biomarker' detects Alzheimer's disease before the onset of symptoms

Croatia, New Mexico (October, 2017): Absence of a prefrontal activation during sensory gating of simple tones detects the Alzheimer's disease (AD) before the occurrence of the first symptoms. Sanja Josef Golubic Ph.D., physicists at the Department of Physics, Faculty of Science, University of Zagreb, reveals the high potential, absolutely non-invasive biomarker of AD pathology in a new study published in the journal Human Brain Mapping. Josef Golubic found a discrete, individual biomarker of AD with "ideal" properties.

Highlights of the new biomarker:

• Absolutely non-invasive
• Detects the illness before the occurrence of the first symptoms (preclinical)
• Discrete: localized/non-localized a prefrontal generator
• Does not require estimation of uniform cut-off levels and standardization processes
• Low sensitivity to individual heterogeneity and variability
• Can follow the evolution of the pathophysiological process of AD
• Individual
• Topographic

Worldwide spread of Alzheimer's disease, a long-lasting morbid type of dementia, is one of the biggest global public health challenges facing this generation. A wealth of evidence emerged during over more than 110 years of disease research suggest that the pathological changes associated with AD start decades before the onset of clinical symptoms. This long progression of neurodegeneration that is irreversible by the stage of symptomatic disease, may account for failure to develop successful disease-modifying therapies. Currently, there is a pressing worldwide search for a marker of very early, possibly reversible, pathological changes related to AD in still cognitively intact individuals, before the occurrence of the first symptoms.

Reisa Sperling, chairman of the National Institute on Aging/Alzheimer's Association Workgroup on Preclinical AD and director of the Neuroimaging Program at Harvard Medical School, reviewing the extensive search for the biomarker of preclinical AD, emphasises: „An active line of research is the relationship of intrinsic neural networks and the "topographic" evolution of the pathophysiological process of AD. It is possible, just as in real estate, that "location, location, location" is key".*

Sanja Josef Golubic found the location of the key - it was hidden in the topography of auditory sensory gating network. She uncovered a topological biomarker of preclinical and clinical AD pathology at the individual level that shows a large effect size (0.98) and high accuracy, sensitivity and specificity (100%) in identifying symptomatic AD patients within a research sample. The new biomarker does not require estimation of cut-off levels or standardization processes what is the main problem with so far proposed AD markers. It is absolutely non-invasive, not based on the use of group means and is not associated with statistically significant changes in a continuous variable. Its strength lies in the simplicity of using a binary value, i.e. activated or not-activated a neural generator. The low sensitivity to individual heterogeneity and variability due to its binary nature is probably the most important property of the proposed biomarker.

"Three years ago we discovered the novel, third fast sensory processing pathway-gating loop, which directly links primary sensory areas to medial prefrontal cortex within first 80ms after auditory stimulation**. We provided strong evidences of the modulatory role of the medial prefrontal generator on the dynamics of generators in primary auditory cortices. We have also noticed the high sensitivity of the gating generators dynamic on AD pathology. It was inspiration to focus our AD biomarker search in the direction of prefrontal sensory gating generator activation", says Sanja Josef Golubic, who together with Cheryl Aine, Selma Supek, Julia Stephen, John Adair and Janice Knoefel form the international research team. The team was formed by the University of Zagreb, New Mexico University, Mind Research Network and New Mexico VA Healthcare System.

"In the present study, we demonstrate the use of the localization of neural sources underlying neuromagnetic fields measured outside a head to detect AD even before the onset of symptoms. The healthy controls activated a prefrontal generator in response to both the deviant and repeating tones of an oddball paradigm. To the contrary, the symptomatic AD group was lacking any medial prefrontal gating generator activation to either the deviant or repeating tones. However, we detected a sub-group of controls characterized by the absence of prefrontal gating generator activation for the repeating tone only and significantly lower scores on a mini mental status exam and delayed visual memory test - Rey-Osterreith Complex Figure Test. It is highly probable that these individuals were captured in a preclinical AD phase since they show both neuropsychological and neurophysiological impairments characteristic of an AD type of dementia, although they did not yet meet clinical criteria for the early phase of symptomatic AD", emphasises Josef Golubic.

The localization of a discrete prefrontal gating activation is a highly promising biomarker of Alzheimer's disease at the individual level with potential of following the evolution of the pathophysiological process of disease. The next steps in evolving the biomarker include the testing in a large independent samples and assessment in longitudinal clinical studies. The large effect size, absolute non-invasiveness and statistical independence, properties of an "ideal" biomarker, will certainly launch this AD biomarker promptly into clinical use.

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Original publication:

"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. Hum Brain Mapp 38:5180-5194, (2017).

This work is funded by:

• National Institutes of Health (NIH). Grant Numbers: R01 AG029495, R01 AG020302
• Department of Energy. Grant Number: DE-FG02-99ER62764
• National Center for Research Resources. Grant Number: 5P20RR021938
• National Institute of General Medical Sciences. Grant Number: 8P20GM103472
• Croatian Ministry of Science, Education and Sport. Grant Number: 199-1081870-1252

References:

*"The Evolution of Preclinical Alzheimer's Disease: Implications for Prevention Trials", Reisa Sperling, Elizabeth Mormino, Keith Johnson.Neuron, 84(3): 608-622 (2014).

** "Modulatory role of the prefrontal generator within the auditory M50 network", Sanja Josef Golubic, Cheryl J Aine, Julia M Stephen, John C Adair, Janice E Knoefel, Selma Supek.Neuroimage 9: 120-131 (2014).

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