Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer's disease

Increasing evidence supports a role for oxidative DNA damage in aging and several neurodegenerative diseases including Alzheimer's disease (AD). Attack of DNA by reactive oxygen species (ROS), particularly hydroxyl radicals, can lead to strand breaks, DNA–DNA and DNA–protein cross-linking, and formation of at least 20 modified bases adducts. In addition, α,β-unsaturated aldehydic by-products of lipid peroxidation including 4-hydroxynonenal and acrolein can interact with DNA bases leading to the formation of bulky exocyclic adducts. Modification of DNA bases by direct interaction with ROS or aldehydes can lead to mutations and altered protein synthesis. Several studies of DNA base adducts in late-stage AD (LAD) brain show elevations of 8-hydroxyguanine (8-OHG), 8-hydroxyadenine (8-OHA), 5-hydroxycytosine (5-OHC), and 5-hydroxyuracil, a chemical degradation product of cytosine, in both nuclear and mitochondrial DNA (mtDNA) isolated from vulnerable regions of LAD brain compared to age-matched normal control subjects. Previous studies also show elevations of acrolein/guanine adducts in the hippocampus of LAD subjects compared to age-matched controls. In addition, studies of base excision repair show a decline in repair of 8-OHG in vulnerable regions of LAD brain. Our recent studies show elevated 8-OHG, 8-OHA, and 5,6-diamino-5-formamidopyrimidine in both nuclear and mtDNA isolated from vulnerable brain regions in amnestic mild cognitive impairment, the earliest clinical manifestation of AD, suggesting that oxidative DNA damage is an early event in AD and is not merely a secondary phenomenon

Oxidative DNA Damage in Mild Cognitive Impairment and Late-Stage Alzheimer\u27s Disease

Increasing evidence supports a role for oxidative DNA damage in aging and several neurodegenerative diseases including Alzheimer\u27s disease (AD). Attack of DNA by reactive oxygen species (ROS), particularly hydroxyl radicals, can lead to strand breaks, DNA–DNA and DNA–protein cross-linking, and formation of at least 20 modified bases adducts. In addition, α,β-unsaturated aldehydic by-products of lipid peroxidation including 4-hydroxynonenal and acrolein can interact with DNA bases leading to the formation of bulky exocyclic adducts. Modification of DNA bases by direct interaction with ROS or aldehydes can lead to mutations and altered protein synthesis. Several studies of DNA base adducts in late-stage AD (LAD) brain show elevations of 8-hydroxyguanine (8-OHG), 8-hydroxyadenine (8-OHA), 5-hydroxycytosine (5-OHC), and 5-hydroxyuracil, a chemical degradation product of cytosine, in both nuclear and mitochondrial DNA (mtDNA) isolated from vulnerable regions of LAD brain compared to age-matched normal control subjects. Previous studies also show elevations of acrolein/guanine adducts in the hippocampus of LAD subjects compared to age-matched controls. In addition, studies of base excision repair show a decline in repair of 8-OHG in vulnerable regions of LAD brain. Our recent studies show elevated 8-OHG, 8-OHA, and 5,6-diamino-5-formamidopyrimidine in both nuclear and mtDNA isolated from vulnerable brain regions in amnestic mild cognitive impairment, the earliest clinical manifestation of AD, suggesting that oxidative DNA damage is an early event in AD and is not merely a secondary phenomenon

Treatment of MCI and Alzheimer\u27s Disease

The present invention provides, among other things, therapeutic compositions and methods that can effectively treat, slow or prevent a neurological disease (e.g., a neurodegenerative disease, e.g., mild cognitive impairment (MCI) or Alzheimer\u27s disease (AD)), in particular, based on therapeutically effective amount of nifedipine, oxidized or nitroso nifedipine derivatives, lactam (e.g., a compound of formula (Ic) or (Ic-i), e.g., NFD-L1), thyroxine (T4), triiodothyronine (T3) and combinations thereof

Process for Detection of Alzheimer\u27s Disease from a Serum Sample

Disclosed is a method of detecting a concentration of a biomarker in a human subject having or being at risk of developing Alzheimer\u27s disease or Mild Cognitive Impairment (MCI). Also disclosed is a process for detecting a concentration of a biomarker in a human subject having or being at risk of developing Alzheimer\u27s disease or Mild Cognitive Impairment (MCI) comprising (a) detecting a first concentration of lipocalin-PDS/TTR complex in a blood sample or urine sample from the subject, (b) determining a second concentration of PDS/TTR complex in a blood sample or urine sample from an unaffected individual, and ( c) comparing the first and second concentrations, wherein a lower first concentration as compared to the second concentration is indicative of the subject having or being at risk of developing Alzheimer\u27s disease

Biomarkers of Mild Cognitive Impairment and Alzheimer\u27s Disease

A method for quantifying a neurodegenerative disorder in a patient that includes obtaining a fluid sample from the subject; measuring a protein biomarker complex in said fluid sample and correlating the measurement with mild cognitive impairment or Alzheimer\u27s disease status. The biomarkers include those that comprise at least one of a transthyretin protein and/or a prostaglandin-H2 D-isomerase protein, and at least one second, different protein selected from a transthyretin, prostaglandin-H2 D-isomerase, beta-2-microglobulin, cystatin C, superoxide dismutase [Cu—Zn], plasma retinol-binding protein, phosphatidylethanolamine-binding protein, carbonic anhydrase 2, prostaglandin-H2 D-isomerase, and/or serotransferrin protein

Single-Base Resolution Mapping of 5-Hydroxymethylcytosine Modifications in Hippocampus of Alzheimer\u27s Disease Subjects

Epigenetic modifications to cytosine have been shown to regulate transcription in cancer, embryonic development, and recently neurodegeneration. While cytosine methylation studies are now common in neurodegenerative research, hydroxymethylation studies are rare, particularly genome-wide mapping studies. As an initial study to analyze 5-hydroxymethylcytosine (5-hmC) in the Alzheimer’s disease (AD) genome, reduced representation hydroxymethylation profiling (RRHP) was used to analyze more than 2 million sites of possible modification in hippocampal DNA of sporadic AD and normal control subjects. Genes with differentially hydroxymethylated regions were filtered based on previously published microarray data for altered gene expression in hippocampal DNA of AD subjects. Our data show significant pathways for altered levels of 5-hmC in the hippocampus of AD subjects compared to age-matched normal controls involved in signaling, energy metabolism, cell function, gene expression, protein degradation, and cell structure and stabilization. Overall, our data suggest a possible role for the dysregulation of epigenetic modifications to cytosine in late stage AD

Methods and Systems for Prognosis and Diagnosis of Brain Damage

The presently-disclosed subject matter includes methods and devices for diagnosing, prognosing, and treating brain damage in a subject, including brain damage caused by stroke or a traumatic brain injury (TBI). The methods can comprise providing a sample obtained from the subject, exposing the sample to an antibody selective for a visinin-like protein, detecting the presence of a complex that includes the antibody and the visinin-like protein, and diagnosing and/or prognosing the subject as having brain damage if there is the presence of the complex. Embodied methods can also comprise administering a treatment for brain damage if the subject includes the presence of the visinin-like protein

The impact of free-streaming on dwarf galaxy counts in low-density regions

We study the statistics of dwarf galaxy populations as a function of environment in the cold dark matter (CDM) and warm dark matter (WDM) cosmogonies, using hydrodynamical simulations starting from initial conditions with matched phases but differing power spectra, and evolved with the EAGLE galaxy formation model. We measure the abundance of dwarf galaxies within 3~Mpc of DM haloes with a present-day halo mass similar to that of the Milky Way (MW), and find that the radial distribution of galaxies $M_{*}>10^7$\Msun is nearly identical for WDM and CDM. However, the cumulative mass function becomes shallower for WDM at lower masses, yielding 50~per~cent fewer dwarf galaxies of $M_{*}\gtrsim10^{5}$~\Msun than CDM. The suppression of low-mass halo counts in WDM relative to CDM increases significantly from high-density regions to low-density regions for haloes in the region of the half-mode mass, M_\rm{hm}. The luminous fraction in the two models also diverges from the overdense to the underdense regions for M>2M_\rm{hm}, as the increased collapse delay at small densities pushes the collapse to after the reionization threshold. However, the stellar mass--halo mass relation of WDM haloes relative to CDM increases towards lower-density regions. Finally, we conclude that the suppression of galaxies with $M_{*}\gtrsim10^5$\Msun between WDM and CDM is independent of density: the suppression of halo counts and the luminous fraction is balanced by an enhancement in stellar mass--halo mass relation.Comment: 10 pages, 6 figures, manuscript to be submitted to MNRA

Speech rhythm auto-recurrence is negatively linked to quality of mental-health counseling interactions

We explored use of Recurrence Quantification Analysis (RQA) of speech rhythm data from mental-health counseling sessions for prediction of quality of psychotherapy. Time-series of inter-syllable intervals (ISIs) were extracted from 239 counseling sessions conducted by 12 therapists who repeatedly interacted with 30 clients. We found a negative association between recurrence metrics and client-rated session quality and a negative link between percent of laminarity and therapist-rated session quality, after controlling for self-reported client depression and distress measures and duration of speech sound within a session. Placing value on reduced recurrence in patterns of ISIs, and especially reduced degree of a dyadic system remaining in the same speech-rhythm pattern may be indicative of a desire for variation in content and strategies of client-therapist interaction. These exploratory findings point to the possibility of RQA-based automated systems to capture the ‘footprint’ of the non-verbal dynamic that is indicative of successful mental-health counseling