**4. Conclusion**

whose 10-year longitudinal study also discerns the dROCF test as highly assertive indicator of conversion to symptomatic phase of Alzheimer's disease, i.e., found significant sensitivity

**Table 1.** Subject scores on the MMSE, dROCFT, mPFC gating generator activation (1-activated, 0-non-activated), clinical

**Subject MMSE dROCFT mPFC standard mPFC deviant Clinical diagnosis Cluster category**

S1 30 26 1 1 H 1 S2 30 25 1 1 H 1 S3 30 23 1 1 H 1 S4 30 23 1 1 H 1 S5 30 22 0 1 H 2 S6 30 22 0 1 H 2 S7 30 17 0 1 H 2 S8 29 26 0 1 MCI 2 S9 29 25 0 1 H 2 S10 29 18 0 1 H 2 S11 26 20 0 1 H 2 S12 26 12 0 0 MCI 3 S13 26 7 0 0 MCI 3 S14 26 1.5 0 0 MCI 3 S15 25 13 0 0 MCI 3 S16 25 0 0 0 AD 3 S17 25 0 0 0 AD 3 S18 24 10.5 0 0 AD 3 S19 23 0 0 0 AD 3 S20 22 2 0 0 AD 3

182 Biomarker - Indicator of Abnormal Physiological Process

The possibility that partial gating activation of the mPFC generator in lower-functioning controls may be associated with preclinical AD phase is also confirmed by several recent findings. There are evidences that reduced functional connectivity affecting the PFC is associated with amyloid-β-related hypersynchronization [107] and p-tau pathology [108] in a very early phase of AD-type memory impairment. The impaired mPFC activity during endogenous brain activity or memory tasks is found in cognitively normal individuals who were AD APOE ε 4 carriers [109]. Also, evidence of decreased extracranial gating dynamics as a predictor of cerebrospinal amyloid-β reduction is demonstrated in MCI patients [65]. Alerted synaptic function along with subsequent synaptic loss and transneuronal spread of pathological tau forms [108] through PFC regions could result in the topological gating deficit that we found in a low-functioning subgroup of controls. This topological gating deficit could reflect a possible

of dROCFT scores to early, possible preclinical AD pathology [106].

diagnosis, and cluster group.

preclinical phase of AD pathology before widespread of cognitive symptoms.

Identification of a novel biomarker of AD (**Figure 4**) with the potential to detect both putative preclinical and clinical stages at the individual subject level represents significant progress toward improving diagnosis of AD and accelerating the field toward the neurobiological advantage of earlier intervention. Although the study engaged only a research sample, the very large effect size (>0.98) of proposed test, thanks to its binary nature, provides high relevance to the finding. Such a large effect size enables this study with the research sample size to yield power greater than 85%.

The new topographic tool certainly has properties, which place it within a group of highpotential biomarkers. The absolute noninvasiveness, individual detection of pathology, ability to detect the preclinical phase of the disease, discrete nature that does not require estimation of uniform cutoff levels and standardization processes, the low sensitivity to individual heterogeneity and variability, capability to follow the evolution of the pathophysiological process of AD, and finally high accuracy and sensitivity make it highly promising

Topological Biomarker of Alzheimer's Disease http://dx.doi.org/10.5772/intechopen.76633 185

However, despite mentioning highlights, the proposed biomarker requires to be tested in a large independent sample and requires assessment in longitudinal clinical MEG studies that would track nonsymptomatic elderly with partial activation of the prefrontal gating generator until the first clinical symptoms appear and finally to autopsy for confirmation of AD. It would also be necessary to investigate prefrontal gating dynamics in other dementias to determine the specificity of novel biomarker to discriminate AD from other etiologies of

[1] Roher A, Wolfe D, Palutke M, KuKuruga D. Purification, ultrastructure, and chemical analysis of Alzheimer disease amyloid plaque core protein. Proceedings of the National

[2] Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubuleassociated protein tau. A component of Alzheimer paired helical filaments. The Journal

[3] Morris GP, Clark IA, Vissel B.Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer's disease. Acta Neuropathologica Communications. 2014;**2**:135

[4] Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta

[5] Braak H, Braak E. Staging of Alzheimer's disease-related neurofibrillary changes.

[6] Bird TD. Genetic factors in Alzheimer's disease. The New England Journal of Medicine.

Academy of Sciences of the United States of America. 1986;**83**:2662-2666

biomarker of AD.

**Author details**

Sanja Josef Golubic

**References**

age-related cognitive decline.

Address all correspondence to: sanja.phy@net.hr

of Biological Chemistry. 1986;**261**:6084-6089

Neuropathologica. 1991;**82**:239-259

2005;**352**:862-864

Neurobiology of Aging. 1995;**16**:271-278

Department of Physics, Faculty of Science, University of Zagreb, Croatia

**Figure 4.** Proposed topological approach as biomarker of AD pathology. Three distinct types of mPFC auditory gating generator activation (red dot) were identified in healthy controls, possible preclinical AD and symptomatic AD patients. The healthy gating topology type requires mPFC activation in processing both oddball tones (standard and deviant). An altered gating topology, characterized by selective mPFC activation only by the deviant tone, presumably represents a presymptomatic phase of AD. Symptomatic AD gating topology lacks mPFC activation for both standard and deviant tones.

Novel topological biomarker, besides high accuracy, sensitivity, and specificity (100%) in identifying symptomatic AD patients in the research sample, shows the potential of following the evolution of the pathophysiological process of disease. The noninvasiveness and low sensitivity to individual heterogeneity and variability due to the discrete nature of impaired prefrontal gating activation are the most important properties of the novel biomarker. It is not based on the use of group means and is not associated with statistically significant changes in a continuous variable. The advantage of this biomarker lies in the simplicity of using a binary value, i.e., activated or not activated a prefrontal generator during gating processing of simple tones. The proposed biomarker is absolutely noninvasive; it is based on recordings of neuromagnetic fields that are produced by normal brain activity.

The new topographic tool certainly has properties, which place it within a group of highpotential biomarkers. The absolute noninvasiveness, individual detection of pathology, ability to detect the preclinical phase of the disease, discrete nature that does not require estimation of uniform cutoff levels and standardization processes, the low sensitivity to individual heterogeneity and variability, capability to follow the evolution of the pathophysiological process of AD, and finally high accuracy and sensitivity make it highly promising biomarker of AD.

However, despite mentioning highlights, the proposed biomarker requires to be tested in a large independent sample and requires assessment in longitudinal clinical MEG studies that would track nonsymptomatic elderly with partial activation of the prefrontal gating generator until the first clinical symptoms appear and finally to autopsy for confirmation of AD. It would also be necessary to investigate prefrontal gating dynamics in other dementias to determine the specificity of novel biomarker to discriminate AD from other etiologies of age-related cognitive decline.
