Brain Network Integrity Changes in Subjective Cognitive Decline: A Possible Physiological Biomarker of Dementia.

Objective: The current study seeks to illustrate potential early and objective neurophysiological biomarkers of neurodegenerative cognitive decline by evaluating features of brain network physiological performance and structure utilizing different modalities. Methods: This study included 17 clinically healthy individuals with self-reported cognitive decline (Subjective Cognitive Decline group, SCD, no objective finding of cognitive decline), 12 individuals diagnosed with amnestic Mild Cognitive Impairment (aMCI), 11 individuals diagnosed with Dementia, and 15 healthy subjects. All subjects underwent computerized cognitive performance testing, MRI scans including T1 for gray matter (GM) volume quantification, DTI for quantification of white matter (WM) microstructure fractional anisotropy (FA) and mean diffusivity (MD), and brain network function evaluation using DELPHI (TMS-EEG) measures of connectivity, excitability, and plasticity. Results: Both DELPHI analysis of network function and DTI analysis detected a significant decrease in connectivity, excitability, and WM integrity in the SCD group compared to healthy control (HC) subjects; a significant decrease was also noted for aMCI and Dementia groups compared to HC. In contrast, no significant decrease was observed in GM volume in the SCD group compared to healthy norms, a significant GM volume decrease was observed only in objectively cognitively impaired aMCI subjects and in dementia subjects. Conclusions: This study results suggest that objective direct measures of brain network physiology and WM integrity may provide early-stage biomarkers of neurodegenerative-related changes in subjects that have not yet displayed any other objective measurable cognitive or GM volume deficits which may facilitate early preventive care for neurodegenerative decline and dementia.

Evaluation of White Matter Integrity Utilizing the DELPHI (TMS-EEG) System.

OBJECTIVE: The aim of this study was to evaluate brain white matter (WM) fibers connectivity damage in stroke and traumatic brain injury (TBI) subjects by direct electrophysiological imaging (DELPHI) that analyzes transcranial magnetic stimulation (TMS)-evoked potentials (TEPs). METHODS: The study included 123 participants, out of which 53 subjects with WM-related pathologies (39 stroke, 14 TBI) and 70 healthy age-related controls. All subjects underwent DELPHI brain network evaluations of TMS-electroencephalogram (EEG)-evoked potentials and diffusion tensor imaging (DTI) scans for quantification of WM microstructure fractional anisotropy (FA). RESULTS: DELPHI output measures show a significant difference between the healthy and stroke/TBI groups. A multidimensional approach was able to classify healthy from unhealthy with a balanced accuracy of 0.81 ± 0.02 and area under the curve (AUC) of 0.88 ± 0.01. Moreover, a multivariant regression model of DELPHI output measures achieved prediction of WM microstructure changes measured by FA with the highest correlations observed for fibers proximal to the stimulation area, such as frontal corpus callosum (r = 0.7 ± 0.02), anterior internal capsule (r = 0.7 ± 0.02), and fronto-occipital fasciculus (r = 0.65 ± 0.03). CONCLUSION: These results indicate that features of TMS-evoked response are correlated to WM microstructure changes observed in pathological conditions, such as stroke and TBI, and that a multidimensional approach combining these features in supervised learning methods serves as a strong indicator for abnormalities and changes in WM integrity.

Introducing a Novel Approach for Evaluation and Monitoring of Brain Health Across Life Span Using Direct Non-invasive Brain Network Electrophysiology.

OBJECTIVE: Evaluation and monitoring of brain health throughout aging by direct electrophysiological imaging (DELPHI) which analyzes TMS (transcranial magnetic stimulation) evoked potentials. METHODS: Transcranial magnetic stimulation evoked potentials formation, coherence and history dependency, measured using electroencephalogram (EEG), was extracted from 80 healthy subjects in different age groups, 25-85 years old, and 20 subjects diagnosed with mild dementia (MD), over 70 years old. Subjects brain health was evaluated using MRI scans, neurocognitive evaluation, and computerized testing and compared to DELPHI analysis of brain network functionality. RESULTS: A significant decrease in signal coherence is observed with age in connectivity maps, mostly in inter-hemispheric temporal, and parietal areas. MD patients display a pronounced decrease in global and inter-hemispheric frontal connectivity compared to healthy controls. Early and late signal slope ratio also display a significant, age dependent, change with pronounced early slope, phase shift, between normal healthy aging, and MD. History dependent analysis demonstrates a binary step function classification of healthy brain vs. abnormal aging subjects mostly for late slope. DELPHI measures demonstrate high reproducibility with reliability coefficients of around 0.9. CONCLUSION: These results indicate that features of evoked response, as charge transfer, slopes of response, and plasticity are altered during abnormal aging and that these fundamental properties of network functionality can be directly evaluated and monitored using DELPHI.

Mutant SOD1 Increases APP Expression and Phosphorylation in Cellular and Animal Models of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease and it is the most common adult onset neurodegenerative disorder affecting motor neurons. There is currently no effective treatment for ALS and our understanding of the pathological mechanism is still far away from prevention and/or treatment of this devastating disease. Amyloid precursor protein (APP) is a transmembrane protein that undergoes processing either by ß-secretase or α-secretase, followed by γ-secretase. In the present study, we show that APP levels, and aberrant phosphorylation, which is associated with enhanced ß-secretase cleavage, are increased in SOD1G93A ALS mouse model. Fluorescence resonance energy transfer (FRET) analysis suggests a close interaction between SOD1 and APP at hippocampal synapses. Notably, SOD1G93A mutation induces APP-SOD1 conformational changes, indicating a crosstalk between these two signaling proteins. Inhibition of APP processing via monoclonal antibody called BBS that blocks APP ß-secretase cleavage site, resulted in reduction of mutant SOD1G93A levels in animal and cellular models of ALS, significantly prolonged life span of SOD1G93A mice and diminished inflammation. Beyond its effect on toxic mutant SOD1G93A, BBS treatment resulted in a reduction in the levels of APP, its processing product soluble APPß and pro-apoptotic p53. This study demonstrates that APP and its processing products contribute to ALS pathology through several different pathways; thus BBS antibody could be a promising neuroprotective strategy for treatment of this disease.

APP homodimers transduce an amyloid-ß-mediated increase in release probability at excitatory synapses.

Accumulation of amyloid-ß peptides (Aß), the proteolytic products of the amyloid precursor protein (APP), induces a variety of synaptic dysfunctions ranging from hyperactivity to depression that are thought to cause cognitive decline in Alzheimer's disease. While depression of synaptic transmission has been extensively studied, the mechanisms underlying synaptic hyperactivity remain unknown. Here, we show that Aß40 monomers and dimers augment release probability through local fine-tuning of APP-APP interactions at excitatory hippocampal boutons. Aß40 binds to the APP, increases the APP homodimer fraction at the plasma membrane, and promotes APP-APP interactions. The APP activation induces structural rearrangements in the APP/Gi/o-protein complex, boosting presynaptic calcium flux and vesicle release. The APP growth-factor-like domain (GFLD) mediates APP-APP conformational changes and presynaptic enhancement. Thus, the APP homodimer constitutes a presynaptic receptor that transduces signal from Aß40 to glutamate release. Excessive APP activation may initiate a positive feedback loop, contributing to hippocampal hyperactivity in Alzheimer's disease.

Spike bursts increase amyloid-ß 40/42 ratio by inducing a presenilin-1 conformational change.

Accumulated genetic evidence suggests that attenuation of the ratio between cerebral amyloid-ß Aß40 and Aß42 isoforms is central to familial Alzheimer's disease (FAD) pathogenesis. However, FAD mutations account for only 1-2% of Alzheimer's disease cases, leaving the experience-dependent mechanisms regulating Aß40/42 an enigma. Here we explored regulation of Aß40/42 ratio by temporal spiking patterns in the rodent hippocampus. Spike bursts boosted Aß40/42 through a conformational change in presenilin1 (PS1), the catalytic subunit of γ-secretase, and subsequent increase in Aß40 production. Conversely, single spikes did not alter basal PS1 conformation and Aß40/42. Burst-induced PS1 conformational shift was mediated by means of Ca(2+)-dependent synaptic vesicle exocytosis. Presynaptic inhibition in vitro and visual deprivation in vivo augmented synaptic and Aß40/42 facilitation by bursts in the hippocampus. Thus, burst probability and transfer properties of synapses represent fundamental features regulating Aß40/42 by experience and may contribute to the initiation of the common, sporadic Alzheimer's disease.

Compartmentalization of the GABAB receptor signaling complex is required for presynaptic inhibition at hippocampal synapses.

Presynaptic inhibition via G-protein-coupled receptors (GPCRs) and voltage-gated Ca(2+) channels constitutes a widespread regulatory mechanism of synaptic strength. Yet, the mechanism of intermolecular coupling underlying GPCR-mediated signaling at central synapses remains unresolved. Using FRET spectroscopy, we provide evidence for formation of spatially restricted (<100 Å) complexes between GABA(B) receptors composed of GB(1a)/GB(2) subunits, Gα(o)ß(1)γ(2) G-protein heterotrimer, and Ca(V)2.2 channels in hippocampal boutons. GABA release was not required for the assembly but for structural reorganization of the precoupled complex. Unexpectedly, GB(1a) deletion disrupted intermolecular associations within the complex. The GB(1a) proximal C-terminal domain was essential for association of the receptor, Ca(V)2.2 and Gßγ, but was dispensable for agonist-induced receptor activation and cAMP inhibition. Functionally, boutons lacking this complex-formation domain displayed impaired presynaptic inhibition of Ca(2+) transients and synaptic vesicle release. Thus, compartmentalization of the GABA(B1a) receptor, Gßγ, and Ca(V)2.2 channel in a signaling complex is required for presynaptic inhibition at hippocampal synapses.

Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses.

Accumulation of cerebral amyloid-beta peptide (Abeta) is essential for developing synaptic and cognitive deficits in Alzheimer's disease. However, the physiological functions of Abeta, as well as the primary mechanisms that initiate early Abeta-mediated synaptic dysfunctions, remain largely unknown. Here we examine the acute effects of endogenously released Abeta peptides on synaptic transfer at single presynaptic terminals and synaptic connections in rodent hippocampal cultures and slices. Increasing extracellular Abeta by inhibiting its degradation enhanced release probability, boosting ongoing activity in the hippocampal network. Presynaptic enhancement mediated by Abeta was found to depend on the history of synaptic activation, with lower impact at higher firing rates. Notably, both elevation and reduction in Abeta levels attenuated short-term synaptic facilitation during bursts in excitatory synaptic connections. These observations suggest that endogenous Abeta peptides have a crucial role in activity-dependent regulation of synaptic vesicle release and might point to the primary pathological events that lead to compensatory synapse loss in Alzheimer's disease.