Limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) often occur in aged brains that also contain appreciable Alzheimer disease neuropathologic changes (ADNC). ...Question has arisen as to whether LATE-NC can occur independently of ADNC. We evaluated data from the University of Kentucky Alzheimer’s Disease Research Center autopsy cohort (383 included subjects) to address 2 questions: (i) Is LATE-NC seen in the absence of ADNC, outside of persons who had the frontotemporal dementia (FTD) clinical syndrome? and (ii) is LATE-NC associated with cognitive impairment across the full spectrum of ADNC severity? In the present study, the pathologic combination of LATE-NC (Stage >1) and low/no ADNC was common: 8.9% (34/383) of all subjects (including demented and non-demented individuals) showed this combination. There were no FTLD-TDP cases to be included from the community-based cohort. Across a broad range of ADNC severity, the presence of LATE-NC was associated with impaired cognition but was never associated with a FTD clinical syndrome.
Spectrally pure lasers, the heart of precision high-end scientific and commercial applications, are poised to make the leap from the laboratory to integrated circuits. Translating this performance to ...integrated photonics will dramatically reduce cost and footprint for applications such as ultrahigh capacity fibre and data centre networks, atomic clocks and sensing. Despite the numerous applications, integrated lasers currently suffer from large linewidth. Brillouin lasers, with their unique properties, offer an intriguing solution, yet bringing their performance to integrated platforms has remained elusive. Here, we demonstrate a sub-hertz (~0.7 Hz) fundamental linewidth Brillouin laser in an integrated Si3N4 waveguide platform that translates advantages of non-integrated designs to the chip scale. This silicon-foundry-compatible design supports low loss from 405 to 2,350 nm and can be integrated with other components. Single- and multiple-frequency output operation provides a versatile low phase-noise solution. We highlight this by demonstrating an optical gyroscope and a low-phase-noise photonic oscillator.
Abstract
Recently, a consensus working group provided new terminology for a common disease entity, limbic predominant age-related TDP-43 encephalopathy (LATE), and its neuropathological substrate ...(LATE-NC). LATE-NC not only often co-occurs with Alzheimer disease neuropathological change (ADNC), but also may present in isolation. The present study aimed to investigate potential risk factors and neuropathological characteristics associated with LATE-NC. A sample of 616 autopsied participants (>75 years at death), with TDP-43 immunohistochemical studies performed, was obtained from the National Alzheimer’s Coordinating Center. Logistic regression analyses examined associations between demographic, clinical and neuropathological characteristics and LATE-NC (TDP-43 in amygdala, hippocampus, or entorhinal/inferior temporal cortex) (alpha = 0.05). Adjusted models indicated that ADNC, hippocampal sclerosis (HS), arteriolosclerosis, and limbic or amygdala-predominant Lewy body disease (LBD), but not other LBD subtypes, were associated with higher odds of LATE-NC, whereas congestive heart failure (CHF) and motor problems as first predominant symptom were associated with lower odds of LATE-NC. Our findings corroborate previous studies indicating associations between LATE-NC and ADNC, HS, and arteriolosclerosis. Novel findings suggest the association with LATE-NC is restricted to amygdala/limbic-predominant subtype of LBD, and a possible protective (or competing risk) association with CHF. This study may inform future hypothesis-driven research on LATE-NC, a common brain disease of aging.
High quality-factor (Q) optical resonators are a key component for ultra-narrow linewidth lasers, frequency stabilization, precision spectroscopy and quantum applications. Integration in a photonic ...waveguide platform is key to reducing cost, size, power and sensitivity to environmental disturbances. However, to date, the Q of all-waveguide resonators has been relegated to below 260 Million. Here, we report a Si
N
resonator with 422 Million intrinsic and 3.4 Billion absorption-limited Qs. The resonator has 453 kHz intrinsic, 906 kHz loaded, and 57 kHz absorption-limited linewidths and the corresponding 0.060 dB m
loss is the lowest reported to date for waveguides with deposited oxide upper cladding. These results are achieved through a careful reduction of scattering and absorption losses that we simulate, quantify and correlate to measurements. This advancement in waveguide resonator technology paves the way to all-waveguide Billion Q cavities for applications including nonlinear optics, atomic clocks, quantum photonics and high-capacity fiber communications.
Iron homeostasis disturbance has been implicated in Alzheimer's disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death ...dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer's mouse model and Alzheimer's patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpn
mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpn
and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.
Autism spectrum disorders (ASD) are a group of biological disorders with associated metabolic derangement. This study aimed to identify a pattern of metabolic perturbance in ASD using metabolomics in ...urinary specimens from 48 children with ASD and 53 age matched controls. Using a combination of liquid- and gas-chromatography-based mass spectrometry, we detected the levels of 82 metabolites (53 of which were increased) that were significantly altered between the ASD and the control groups using osmolality normalized data. Pattern analysis showed that the levels of several amino acids such as glycine, serine, threonine, alanine, histidine, glutamyl amino acids and the organic acid, taurine were significantly (p ≤ 0.05) lower in ASD children. The levels of antioxidants such as carnosine were also reduced in ASD (p = 0.054). Furthermore, several gut bacterial metabolites were significantly altered in ASD children who had gastrointestinal dysfunction. Overall, this study detected abnormal amino acid metabolism, increased oxidative stress, and altered gut microbiomes in ASD. The relationship of altered gut microbial co-metabolism and the disrupted metabolisms requires further investigation.
We review the literature on Tau and TDP-43 proteinopathies in aged human brains and the relevant underlying pathogenetic cascades. Complex interacting pathways are implicated in Alzheimer's disease ...and related dementias (ADRD), wherein multiple proteins tend to misfold in a manner that is “reactive,” but, subsequently, each proteinopathy may contribute strongly to the clinical symptoms. Tau proteinopathy exists in brains of individuals across a broad spectrum of primary underlying conditions—e.g., developmental, traumatic, and inflammatory/infectious diseases. TDP-43 proteinopathy is also expressed in a wide range of clinical disorders. Although TDP-43 proteinopathy was first described in the central nervous system of patients with amyotrophic lateral sclerosis (ALS) and in subtypes of frontotemporal dementia (FTD/FTLD), TDP-43 proteinopathy is also present in chronic traumatic encephalopathy, cognitively impaired persons in advanced age with hippocampal sclerosis, Huntington's disease, and other diseases. We list known Tau and TDP-43 proteinopathies. There is also evidence of cellular co-localization between Tau and TDP-43 misfolded proteins, suggesting common pathways or protein interactions facilitating misfolding in one protein by the other. Multiple pleiotropic gene variants can alter risk for Tau or TDP-43 pathologies, and certain gene variants (e.g., APOE ε4, Huntingtin triplet repeats) are associated with increases of both Tau and TDP-43 proteinopathies. Studies of genetic risk factors have provided insights into multiple nodes of the pathologic cascades involved in Tau and TDP-43 proteinopathies. Variants from a specific gene can be either a low-penetrant risk factor for a group of diseases, or alternatively, a different variant of the same gene may be a disease-driving allele that is associated with a relatively aggressive and early-onset version of a clinically and pathologically specific disease type. Overall, a complex but enlightening paradigm has emerged, wherein both Tau and TDP-43 proteinopathies are linked to numerous overlapping upstream influences, and both are associated with multiple downstream pathologically- and clinically-defined deleterious effects.
LATE‐NC is a diagnostic term developed by a large, multidisciplinary, international team of experts, after months of discussion and a NIH‐funded 2 day in‐person meeting in late 2018. This group was ...tasked with generating suitable terminology for common TDP‐43 proteinopathy in aging. When diagnosing an unusual case of TDP‐43 proteinopathy at autopsy, a diagnostic approach is recommended that is analogous to unusual tauopathy or α‐synucleinopathy cases: render a descriptive neuropathologic diagnosis, rather than label such cases as LATE‐NC.
Ribosomal deficits are documented in mild cognitive impairment (MCI), which often represents an early stage Alzheimer's disease (AD), as well as in advanced AD. The nucleolar rRNA genes (rDNA), ...transcription of which is critical for ribosomal biogenesis, are regulated by epigenetic silencing including promoter CpG methylation.
To assess whether CpG methylation of the rDNA promoter was dysregulated across the AD spectrum, we analyzed brain samples from 10 MCI-, 23 AD-, and, 24 age-matched control individuals using bisulfite mapping. The rDNA promoter became hypermethylated in cerebro-cortical samples from MCI and AD groups. In parietal cortex, the rDNA promoter was hypermethylated more in MCI than in advanced AD. The cytosine methylation of total genomic DNA was similar in AD, MCI, and control samples. Consistent with a notion that hypermethylation-mediated silencing of the nucleolar chromatin stabilizes rDNA loci, preventing their senescence-associated loss, genomic rDNA content was elevated in cerebrocortical samples from MCI and AD groups.
In conclusion, rDNA hypermethylation could be a new epigenetic marker of AD. Moreover, silencing of nucleolar chromatin may occur during early stages of AD pathology and play a role in AD-related ribosomal deficits and, ultimately, dementia.
Abstract
Over the course of most common neurodegenerative diseases the amygdala accumulates pathologically misfolded proteins. Misfolding of 1 protein in aged brains often is accompanied by the ...misfolding of other proteins, suggesting synergistic mechanisms. The multiplicity of pathogenic processes in human amygdalae has potentially important implications for the pathogenesis of Alzheimer disease, Lewy body diseases, chronic traumatic encephalopathy, primary age-related tauopathy, and hippocampal sclerosis, and for the biomarkers used to diagnose those diseases. Converging data indicate that the amygdala may represent a preferential locus for a pivotal transition from a relatively benign clinical condition to a more aggressive disease wherein multiple protein species are misfolded. Thus, understanding of amygdalar pathobiology may yield insights relevant to diagnoses and therapies; it is, however, a complex and imperfectly defined brain region. Here, we review aspects of amygdalar anatomy, connectivity, vasculature, and pathologic involvement in neurodegenerative diseases with supporting data from the University of Kentucky Alzheimer's Disease Center autopsy cohort. Immunohistochemical staining of amygdalae for Aβ, Tau, α-synuclein, and TDP-43 highlight the often-coexisting pathologies. We suggest that the amygdala may represent an "incubator" for misfolded proteins and that it is possible that misfolded amygdalar protein species are yet to be discovered.
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