Time saved in activities of daily living and whole-brain volume: Post hoc analysis of a randomized feasibility trial of gamma oscillation treatment in participants with mild or moderate Alzheimer's disease.

Introduction: Gamma oscillations in the brain are necessary for normal cognitive function, sensory processing, and memory consolidation, and are reduced in Alzheimer's disease (AD). In a 6 month, randomized, feasibility trial in participants with mild-to-moderate AD (OVERTURE [NCT03556280],  = 76), a non-invasive method for sensory-evoked brain gamma oscillations outperformed sham on the secondary outcomes of slowing decline on the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) functional scale, magnetic resonance imaging measures of whole brain volume and the Mini-Mental State Examination (MMSE) cognitive outcome, despite not showing statistical significance on the primary outcome (Mild and Moderate Alzheimer's Disease Composite [MADCOMS]), a composite cognitive-functional score. In this post hoc analysis of OVERTURE, we evaluated the effects of investigational sensory-evoked gamma oscillation treatment in terms of time saved, as an estimate of slowing in disease progression, on ADCS-ADL, MMSE, and whole-brain volume.

A novel method for harmonization of PET image spatial resolution without phantoms.

Background: Estimation of the spatial resolution in real images is extremely important in several fields, including crystallography, optics, microscopy, and tomography. In human PET imaging, estimating spatial resolution typically involves the acquisition of images from a physical phantom, typically a Hoffman phantom, which poses a logistical burden, especially in large multi-center studies. Indeed, phantom images may not always be readily available, and this method requires constant monitoring of scanner updates or replacements, scanning protocol changes, and image reconstruction guidelines to establish a equivalence with scans acquired from human subjects.

Alpha rhythm and Alzheimer's disease: Has Hans Berger's dream come true?

In this "centenary" paper, an expert panel revisited Hans Berger's groundbreaking discovery of human restingstate electroencephalographic (rsEEG) alpha rhythms (8-12 Hz) in 1924, his foresight of substantial clinical applications in patients with "senile dementia," and new developments in the field, focusing on Alzheimer's disease (AD), the most prevalent cause of dementia in pathological aging. Clinical guidelines issued in 2024 by the US National Institute on Aging-Alzheimer's Association (NIA-AA) and the European Neuroscience Societies did not endorse routine use of rsEEG biomarkers in the clinical workup of older adults with cognitive impairment. Nevertheless, the expert panel highlighted decades of research from independent workgroups and different techniques showing consistent evidence that abnormalities in rsEEG delta, theta, and alpha rhythms (< 30 Hz) observed in AD patients correlate with wellestablished AD biomarkers of neuropathology, neurodegeneration, and cognitive decline.

CSF proteomics reveals changes in myelin and synaptic biology after Spectris treatment.

Introduction: Brain steady-state gamma oscillations evoked using a non-invasive medical device (Spectris) have shown potential clinical benefits in patients with mild-moderate Alzheimer's disease (AD), including reduced functional and cognitive decline, reduced brain volume and myelin loss, and increased brain functional connectivity. We analyzed changes in cerebrospinal fluid (CSF) proteins after Spectris treatment in mild cognitive impairment (MCI) and their relationship to established biological pathways implicated in AD.

Methods: Unbiased proteomic analysis of CSF samples from participants with amyloid-positive MCI ( = 10) was conducted from the FLICKER (NCT03543878) clinical trial.

Spectris™ treatment preserves corpus callosum structure in Alzheimer's disease.

Objective: To examine the impact of 40Hz gamma stimulation on the preservation of the corpus callosum, a critical structure for interhemispheric connectivity, in people with mild cognitive impairment or Alzheimer's disease.

Methods: OVERTURE (NCT03556280) participants were randomized 2:1 (Active:Sham) to receive daily, 1-h, 40Hz gamma sensory stimulation or sham treatment for 6 months. Structural magnetic resonance imaging data were analyzed to assess changes in corpus callosum area ( = 50; 33 for active, 17 for sham).

Parallel electrophysiological abnormalities due to COVID-19 infection and to Alzheimer's disease and related dementia.

Many coronavirus disease 2019 (COVID-19) positive individuals exhibit abnormal electroencephalographic (EEG) activity reflecting "brain fog" and mild cognitive impairments even months after the acute phase of infection. Resting-state EEG abnormalities include EEG slowing (reduced alpha rhythm; increased slow waves) and epileptiform activity. An expert panel conducted a systematic review to present compelling evidence that cognitive deficits due to COVID-19 and to Alzheimer's disease and related dementia (ADRD) are driven by overlapping pathologies and neurophysiological abnormalities.

Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease.

Background: Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation.

Noninvasive Gamma Sensory Stimulation May Reduce White Matter and Myelin Loss in Alzheimer's Disease.

Background: Patients with Alzheimer's disease (AD) demonstrate progressive white matter atrophy and myelin loss. Restoring myelin content or preventing demyelination has been suggested as a therapeutic approach for AD.

Objective: Herein, we investigate the effects of non-invasive, combined visual and auditory gamma-sensory stimulation on white matter atrophy and myelin content loss in patients with AD.

Positive allosteric modulators of the α7 nicotinic acetylcholine receptor: SAR investigation around PNU-120596.

The α7 nicotinic acetylcholine receptor is a calcium permeable, ligand-gated ion channel that modulates synaptic transmission in the hippocampus, thalamus, and cerebral cortex. Previously disclosed work described PNU-120596 that acts as a powerful positive allosteric modulator of the α7 nicotinic acetylcholine receptor. The initial structure-activity relationships around PNU-120596 were gleaned from screening a large thiazole library.

Treatment effects on event-related EEG potentials and oscillations in Alzheimer's disease.

Alzheimer's disease dementia (ADD) is the most diffuse neurodegenerative disorder belonging to mild cognitive impairment (MCI) and dementia in old persons. This disease is provoked by an abnormal accumulation of amyloid-beta and tauopathy proteins in the brain. Very recently, the first disease-modifying drug has been licensed with reserve (i.

Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer's Disease Patients.

Pathological proteins contributing to Alzheimer's disease (AD) are known to disrupt normal neuronal functions in the brain, leading to unbalanced neuronal excitatory-inhibitory tone, distorted neuronal synchrony, and network oscillations. However, it has been proposed that abnormalities in neuronal activity directly contribute to the pathogenesis of the disease, and in fact it has been demonstrated that induction of synchronized 40 Hz gamma oscillation of neuronal networks by sensory stimulation reverses AD-related pathological markers in transgenic mice carrying AD-related human pathological genes. Based on these findings, the current study evaluated whether non-invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for AD patients.

TREM2 Deficiency Disrupts Network Oscillations Leading to Epileptic Activity and Aggravates Amyloid-β-Related Hippocampal Pathophysiology in Mice.

Background: Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer's disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology.

Recommendations for Preclinical Testing of Treatments Against Alzheimer's Disease-Related Epileptiform Spikes in Transgenic Rodent Models.

Recent evidence suggests that about 30%of patients with mild to moderate Alzheimer's disease (AD) without a known diagnosis of epilepsy may display epileptiform spikes during electroencephalographic (EEG) recordings. These abnormal discharges occur predominantly during sleep and may be associated with accelerated disease progression. Subclinical spikes may represent a relevant target for clinical drug interventions, and there is a clear unmet need for preclinical testing of novel disease modifying agents in suitable animal models.

Therapy for Alzheimer's disease: Missing targets and functional markers?

The development of the next generation therapy for Alzheimer's disease (AD) presents a huge challenge given the number of promising treatment candidates that failed in trials, despite recent advancements in understanding of genetic, pathophysiologic and clinical characteristics of the disease. This review reflects some of the most current concepts and controversies in developing disease-modifying and new symptomatic treatments. It elaborates on recent changes in the AD research strategy for broadening drug targets, and potentials of emerging non-pharmacological treatment interventions.

Developmental synaptic regulator, TWEAK/Fn14 signaling, is a determinant of synaptic function in models of stroke and neurodegeneration.

Identifying molecular mediators of neural circuit development and/or function that contribute to circuit dysfunction when aberrantly reengaged in neurological disorders is of high importance. The role of the TWEAK/Fn14 pathway, which was recently reported to be a microglial/neuronal axis mediating synaptic refinement in experience-dependent visual development, has not been explored in synaptic function within the mature central nervous system. By combining electrophysiological and phosphoproteomic approaches, we show that TWEAK acutely dampens basal synaptic transmission and plasticity through neuronal Fn14 and impacts the phosphorylation state of pre- and postsynaptic proteins in adult mouse hippocampal slices.

Characterization of Vixotrigine, a Broad-Spectrum Voltage-Gated Sodium Channel Blocker.

Voltage-gated sodium channels (Navs) are promising targets for analgesic and antiepileptic therapies. Although specificity between Nav subtypes may be desirable to target specific neural types, such as nociceptors in pain, many broadly acting Nav inhibitors are clinically beneficial in neuropathic pain and epilepsy. Here, we present the first systematic characterization of vixotrigine, a Nav blocker.

Characterization of PF-6142, a Novel, Non-Catecholamine Dopamine Receptor D1 Agonist, in Murine and Nonhuman Primate Models of Dopaminergic Activation.

Selective activation of dopamine D1 receptors remains a promising pro-cognitive therapeutic strategy awaiting robust clinical investigation. PF-6142 is a key example from a recently disclosed novel series of non-catechol agonists and partial agonists of the dopamine D1/5 receptors (D1R) that exhibit pharmacokinetic (PK) properties suitable for oral delivery. Given their reported potential for functionally biased signaling compared to known catechol-based selective agonists, and the promising rodent PK profile of PF-6142, we utilized relevant assays in male rodents and male and female non-human primates (NHP) to evaluate the pharmacology of this new series.

Impaired hypocretin/orexin system alters responses to salient stimuli in obese male mice.

The brain has evolved in an environment where food sources are scarce, and foraging for food is one of the major challenges for survival of the individual and species. Basic and clinical studies show that obesity or overnutrition leads to overwhelming changes in the brain in animals and humans. However, the exact mechanisms underlying the consequences of excessive energy intake are not well understood.

What electrophysiology tells us about Alzheimer's disease: a window into the synchronization and connectivity of brain neurons.

Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer's disease (AD), despite a surge in recent validated evidence. This position paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.

Age-dependent emergence of neurophysiological and behavioral abnormalities in progranulin-deficient mice.

Background: Loss-of-function mutations in the progranulin gene cause frontotemporal dementia, a genetic, heterogeneous neurodegenerative disorder. Progranulin deficiency leads to extensive neuronal loss in the frontal and temporal lobes, altered synaptic connectivity, and behavioral alterations.

Methods: The chronological emergence of neurophysiological and behavioral phenotypes of Grn heterozygous and homozygous mice in the dorsomedial thalamic-medial prefrontal cortical pathway were evaluated by in vivo electrophysiology and reward-seeking/processing behavior, tested between ages 3 and 12.

Evoked potentials as a translatable biomarker to track functional remyelination.

Enhancing remyelination is a key therapeutic strategy for demyelinating diseases such as multiple sclerosis. To achieve this goal, a central challenge is being able to quantitatively and longitudinally track functional remyelination, especially with translatable biomarkers that can be performed in both preclinical models and in the clinic. We developed the methodology to stably measure multi-modal sensory evoked potentials from the skull surface over the course of months in individual mice and applied it to a genetic mouse model of oligodendrocyte ablation and demyelination.

Neurophysiological signals as predictive translational biomarkers for Alzheimer's disease treatment: effects of donepezil on neuronal network oscillations in TgF344-AD rats.

Background: Translational research in Alzheimer's disease (AD) pathology provides evidence that accumulation of amyloid-β and hyperphosphorylated tau, neuropathological hallmarks of AD, is associated with complex disturbances in synaptic and neuronal function leading to oscillatory abnormalities in the neuronal networks that support memory and cognition. Accordingly, our recent study on transgenic TgF344-AD rats modeling AD showed an age-dependent reduction of stimulation-induced oscillations in the hippocampus, and disrupted long-range connectivity together with enhanced neuronal excitability in the cortex, reflected in greatly increased expression of high-voltage spindles, an epileptic absence seizure-like activity. To better understand the translational value of observed oscillatory abnormalities in these rats, we examine here the effects of donepezil, an acetylcholine esterase inhibitor clinically approved for AD treatment.

Altered Cortical and Hippocampal Excitability in TgF344-AD Rats Modeling Alzheimer's Disease Pathology.

Current findings suggest that accumulation of amyloid-β (Aβ) and hyperphosphorylated tau in the brain disrupt synaptic function in hippocampal-cortical neuronal networks leading to impairment in cognitive and affective functions in Alzheimer's disease (AD). Development of new disease-modifying AD drugs are challenging due to the lack of predictive animal models and efficacy assays. In the present study we recorded neural activity in TgF344-AD rats, a transgenic model with a full array of AD pathological features, including age-dependent Aβ accumulation, tauopathy, neuronal loss, and cognitive impairments.

Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans.

Cannabis use has been associated with altered sensory gating and neural oscillations. However, it is unclear which constituent in cannabis is responsible for these effects, or whether these are cannabinoid receptor 1 (CB1R) mediated. Therefore, the present study in humans and rats examined whether cannabinoid administration would disrupt sensory gating and evoked oscillations utilizing electroencephalography (EEG) and local field potentials (LFPs), respectively.