Developing Topics.

Background: Retrotransposon-derived extrachromosomal circular DNA (eccDNA) was extracted and sequenced from brains with Alzheimer's disease, progressive supranuclear palsy, or healthy controls. Retrotransposon-derived DNA was visualized outside of the nucleus in these phenotypes with phospho-STING. Drosophila were used as a model to study extranuclear retrotransposon DNA.

Developing Topics.

Background: Addition of apolipoprotein E4 (ApoE4) proteotype (as a surrogate for high-risk APOE ɛ4 genotype) has significantly improved models that use the plasma Aβ42/40 ratio to predict Aβ PET-positivity, but studies suggest different ethnicities may be less affected by the addition. Our objective was to assess the influence ApoE4 proteotype in a predominantly Hispanic cohort of participants.

Method: Participants in this study (n = 250) underwent neurological and neuropsychological evaluations and amyloid PET brain scans (SUVR data and visual reads) at the 1Florida ADRC; they also underwent blood draws for ApoE4 proteotyping and Aβ42/40 ratio determination by LC-MS/MS performed at Quest Diagnostics.

Developing Topics.

Background: Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30-120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. High temporal resolution recording methods, such as magnetoencephalography, have made it clear that Alzheimer's disease (AD) patients, starting as early as the mild cognitive impairment (MCI) stage, have diminished γ-oscillations even before the Aβ load takes full effect.

A therapeutic small molecule enhances γ-oscillations and improves cognition/memory in Alzheimer's disease model mice.

Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimer's disease (AD).

α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden.

Introduction: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains.

Methods: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo.

A pilot study to investigate the safety and feasibility of antiretroviral therapy for Alzheimer's disease (ART-AD).

Retrotransposons are viral-like DNA sequences that constitute approximately 41% of the human genome. Studies in mice, cultured cells, and human brain indicate that retrotransposons are activated in settings of tauopathy, including Alzheimer's disease, and causally drive neurodegeneration. The anti-retroviral medication 3TC (lamivudine), a nucleoside analog reverse transcriptase inhibitor, limits retrotransposon activation and suppresses neurodegeneration in tau transgenic two mouse models of tauopathy, and in brain assembloids derived from patients with sporadic Alzheimer's disease.

Association between pre-dementia psychiatric diagnoses and all-cause dementia is independent from polygenic dementia risks in the UK Biobank.

Background: Psychiatric disorders have been associated with higher risk for future dementia. Understanding how pre-dementia psychiatric disorders (PDPD) relate to established dementia genetic risks has implications for dementia prevention.

Methods: In this retrospective cohort study, we investigated the relationships between polygenic risk scores for Alzheimer's disease (AD PRS), PDPD, alcohol use disorder (AUD), and subsequent dementia in the UK Biobank (UKB) and tested whether the relationships are consistent with different causal models.

Cortical Synchrony and Information Flow during Transition from Wakefulness to Light Non-Rapid Eye Movement Sleep.

Sleep is a highly stereotyped phenomenon, requiring robust spatiotemporal coordination of neural activity. Understanding how the brain coordinates neural activity with sleep onset can provide insights into the physiological functions subserved by sleep and the pathologic phenomena associated with sleep onset. We quantified whole-brain network changes in synchrony and information flow during the transition from wakefulness to light non-rapid eye movement (NREM) sleep, using MEG imaging in a convenient sample of 14 healthy human participants (11 female; mean 63.

Distinct Patterns of Gene Expression Changes in the Colon and Striatum of Young Mice Overexpressing Alpha-Synuclein Support Parkinson's Disease as a Multi-System Process.

Background: Evidence supports a role for the gut-brain axis in Parkinson's disease (PD). Mice overexpressing human wild type α- synuclein (Thy1-haSyn) exhibit slow colonic transit prior to motor deficits, mirroring prodromal constipation in PD. Identifying molecular changes in the gut could provide both biomarkers for early diagnosis and gut-targeted therapies to prevent progression.

The effects of enhancing angiotensin converting enzyme in myelomonocytes on ameliorating Alzheimer's-related disease and preserving cognition.

This review examines the role of angiotensin-converting enzyme (ACE) in the context of Alzheimer's disease (AD) and its potential therapeutic value. ACE is known to degrade the neurotoxic 42-residue long alloform of amyloid β-protein (Aβ), a peptide strongly associated with AD. Previous studies in mice, demonstrated that targeted overexpression of ACE in CD115 myelomonocytic cells (ACE10 models) improved their immune responses to effectively reduce viral and bacterial infection, tumor growth, and atherosclerotic plaque.

Re-Engaging Individuals & Societies for Structural Evolution: A Brain Health Equity Neuropsychology Research Framework.

Objective: A brain health equity neuropsychology research framework (NRF) is crucial to the anti-racist movement in cognitive assessments. Universalist interpretation of neuropsychological tools contributes to systemic disparities, and there is a need for a clear conceptual framework for disentangling the direct and indirect impact of social determinants of health (SDH) on brain-behavior relationships and neuropsychological performance. The aim of this paper is to present a NRF anchored in the principles of brain health and health equity that is inclusive, and can be implemented across racially and ethnically diverse communities.

Foundational Curriculum and Core Guidelines for Training in Latinx/a/o-Hispanic Cultural Neuropsychology Across the Lifespan.

Objective: The training competency of individual and cultural diversity is an advanced, fundamental competency to health service psychology since 2015. However, there is minimal instruction on how to integrate it into training curricula in neuropsychology, especially at the postdoctoral fellowship level. Our objective was to operationalize the individual and cultural diversity standard to provide a tangible application for educational programs on how to develop a competency-based training model for Latinx/a/o-Hispanic (L/H) cultural neuropsychology across the lifespan.

Pharmacological Inhibition of p-21 Activated Kinase (PAK) Restores Impaired Neurite Outgrowth and Remodeling in a Cellular Model of Down Syndrome.

Down syndrome (DS) is characterized by the trisomy of chromosome 21 and by cognitive deficits that have been related to neuronal morphological alterations in humans, as well as in animal models. The gene encoding for amyloid precursor protein (APP) is present in autosome 21, and its overexpression in DS has been linked to neuronal dysfunction, cognitive deficit, and Alzheimer's disease-like dementia. In particular, the neuronal ability to extend processes and branching is affected.

Extracellular CIRP Induces Calpain Activation in Neurons via PLC-IP-Dependent Calcium Pathway.

Abnormal calcium homeostasis, activation of protease calpain, generation of p25 and hyperactivation of cyclin-dependent kinase 5 (Cdk5) have all been implicated in the pathogenesis of neurogenerative diseases including Alzheimer's disease. We have recently shown that extracellular cold-inducible RNA-binding protein (eCIRP) induces Cdk5 activation via p25. However, the precise molecular mechanism by which eCIRP regulates calcium signaling and calpain remains to be addressed.

Alzheimer's disease phenotypes show different sleep architecture.

Introduction: Sleep-wake disturbances are a prominent feature of Alzheimer's disease (AD). Atypical (non-amnestic) AD syndromes have different patterns of cortical vulnerability to AD. We hypothesized that atypical AD also shows differential vulnerability in subcortical nuclei that will manifest as different patterns of sleep dysfunction.

Culturally Competent Assessment of Neurocognitive Functioning in Latinos with Complex Multimorbidity: A Case Study.

Multimorbidity-the coexistence of multiple chronic conditions within an individual-is the new normal in hospital settings. Individuals with higher levels of multimorbidity require a multidisciplinary and holistic approach to meet their needs, though the complexity of their neurocognitive profiles is still poorly researched. This study reported on the neurocognitive profile of a 69-year-old, left-handed, Latino cisgender male with 10 years of education.

Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer's disease.

Background: Neuronal- and circuit-level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (Aβ) in preclinical models of Alzheimer's disease (AD). These relationships remain poorly understood in patients with AD.

Methods: Using empirical spectra from magnetoencephalography and computational modeling (neural mass model), we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and Aβ, measured by positron emission tomography, in patients with AD.

Neuronal synchrony abnormalities associated with subclinical epileptiform activity in early-onset Alzheimer's disease.

Since the first demonstrations of network hyperexcitability in scientific models of Alzheimer's disease, a growing body of clinical studies have identified subclinical epileptiform activity and associated cognitive decline in patients with Alzheimer's disease. An obvious problem presented in these studies is lack of sensitive measures to detect and quantify network hyperexcitability in human subjects. In this study we examined whether altered neuronal synchrony can be a surrogate marker to quantify network hyperexcitability in patients with Alzheimer's disease.

Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial.

Importance: Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).

Objective: To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.

Design, Setting, And Participants: The Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020.

Reduced synchrony in alpha oscillations during life predicts post mortem neurofibrillary tangle density in early-onset and atypical Alzheimer's disease.

Introduction: Neurophysiological manifestations selectively associated with amyloid beta and tau depositions in Alzheimer's disease (AD) are useful network biomarkers to identify peptide specific pathological processes. The objective of this study was to validate the associations between reduced neuronal synchrony within alpha oscillations and neurofibrillary tangle (NFT) density in autopsy examination, in patients with AD.

Methods: In a well-characterized clinicopathological cohort of AD patients (n = 13), we quantified neuronal synchrony within alpha (8-12 Hz) and delta-theta (2-8 Hz) oscillations, using magnetoencephalography during the disease course, within six selected neocortical and hippocampal regions, including angular gyrus, superior temporal gurus, middle frontal gyrus, primary motor cortex, CA1, and subiculum, and correlated these with regional NFT density quantified at histopathological examination.

Case Report: Early-Onset Behavioral Variant Frontotemporal Dementia in Patient With Retrotransposed Full-Length Transcript of Variant 5.

Frontotemporal dementia (FTD) rarely occurs in individuals under the age of 30, and genetic causes of early-onset FTD are largely unknown. The current report follows a 27 year-old patient with no significant past medical history presenting with two years of progressive changes in behavior, rushed speech, verbal aggression, and social withdrawal. MRI and FDG-PET imaging of the brain revealed changes maximally in the frontal and temporal lobes, which along with the clinical features, are consistent with behavioral variant FTD.