High-Performance Liquid Chromatography Assay for Moxifloxacin in Brain Tissue and Plasma: Validation in a Pharmacokinetic Study in a Murine Model of Cerebral Listeriosis

Moxifloxacin is a broad-spectrum antibacterial 8-methoxy-fluoroquinolone. In order to evaluate the pharmacokinetic properties of moxifloxacin in mouse plasma and brain tissue, we developed a high-performance liquid chromatography (HPLC) method. This study was based on single-drug delivery, intravenously dosed in a central listeriosis murine model. The method employed a reversed-phase Lichrospher RP-18 with a precolumn (250 × 4.6 mm) and a mobile phase composed of a mixture of acetonitrile, methanol, and citric buffer (pH = 3.5) with sodium dodecyl sulfate and tetrabutylammonium bromide. Fluorescence detection was performed at an excitation wavelength of 290 nm and an emission wavelength of 550 nm. The relative standard deviation of intra- and inter-day assays was <10%. This validated method led to a short retention time (8.0 min) for moxifloxacin. The standard curves were linear from 5–250 μg/L in plasma and from 0.1–2.5 μg/g of brain tissue. The limits of quantification were 5 μg/L in plasma and 0.1 μg/g in brain tissue. The method enabled the detection of systemic antimicrobial in plasma and in CNS in Listeria-infected mice. Injected moxifloxacin passed through the encephalic barrier within a 30 to 60 min after injection time frame. Moxifloxacin pharmacokinetics are modeled in an infected model compared to control mice

Cerebrovascular Pathology in Down Syndrome and Alzheimer Disease

People with Down syndrome (DS) are at high risk for developing Alzheimer disease (AD) with age. Typically, by age 40 years, most people with DS have sufficient neuropathology for an AD diagnosis. Interestingly, atherosclerosis and hypertension are atypical in DS with age, suggesting the lack of these vascular risk factors may be associated with reduced cerebrovascular pathology. However, because the extra copy of APP leads to increased beta-amyloid peptide (Aβ) accumulation in DS, we hypothesized that there would be more extensive and widespread cerebral amyloid angiopathy (CAA) with age in DS relative to sporadic AD. To test this hypothesis CAA, atherosclerosis and arteriolosclerosis were used as measures of cerebrovascular pathology and compared in post mortem tissue from individuals with DS (n = 32), sporadic AD (n = 80) and controls (n = 37). CAA was observed with significantly higher frequencies in brains of individuals with DS compared to sporadic AD and controls. Atherosclerosis and arteriolosclerosis were rare in the cases with DS. CAA in DS may be a target for future interventional clinical trials

Distribution of Microglial Phenotypes as a Function of Age and Alzheimer\u27s Disease Neuropathology in the Brains of People with Down Syndrome

Introduction: Microglial cells play an important role in the development of Alzheimer\u27s disease (AD). People with Down syndrome (DS) inevitably develop AD neuropathology (DSAD) by 40 years of age. We characterized the distribution of different microglial phenotypes in the brains of people with DS and DSAD. Methods: Autopsy tissue from the posterior cingulate cortex (PCC) from people with DS, DSAD, and neurotypical controls was immunostained with the microglial marker Iba1 to assess five microglia morphological types. Results: Individuals with DS have more hypertrophic microglial cells in their white matter. In the gray matter, individuals with DSAD had significantly fewer ramified microglia and more dystrophic microglia than controls and the younger individuals with DS. The DSAD group also exhibited more rod-shaped and amoeboid cells than the AD group. Discussion: Individuals with DS and DSAD show a microglial phenotype that distinguishes them from non-DS controls

Cognitive and Behavioral Domains That Reliably Differentiate Normal Aging and Dementia in Down Syndrome

Primary care integration of Down syndrome (DS)-specific dementia screening is strongly advised. The current study employed principal components analysis (PCA) and classification and regression tree (CART) analyses to identify an abbreviated battery for dementia classification. Scale- and subscale-level scores from 141 participants (no dementia n = 68; probable Alzheimer’s disease n = 73), for the Severe Impairment Battery (SIB), Dementia Scale for People with Learning Disabilities (DLD), and Vineland Adaptive Behavior Scales—Second Edition (Vineland-II) were analyzed. Two principle components (PC1, PC2) were identified with the odds of a probable dementia diagnosis increasing 2.54 times per PC1 unit increase and by 3.73 times per PC2 unit increase. CART analysis identified that the DLD sum of cognitive scores (SCS \u3c 35 raw) and Vineland-II community subdomain (\u3c 36 raw) scores best classified dementia. No significant difference in the PCA versus CART area under the curve (AUC) was noted (D(65.196) = −0.57683; p = 0.57; PCA AUC = 0.87; CART AUC = 0.91). The PCA sensitivity was 80% and specificity was 70%; CART was 100% and specificity was 81%. These results support an abbreviated dementia screening battery to identify at-risk individuals with DS in primary care settings to guide specialized diagnostic referral

Down Syndrome: Age-Dependence of PiB Binding in Postmortem Frontal Cortex Across the Lifespan

Beta-amyloid (Aβ) deposition in brain accumulates as a function of age in people with Down syndrome (DS) with subsequent development into Alzheimer disease neuropathology, typically by 40 years of age. In vivo imaging using the Pittsburgh Compound B (PiB) ligand has facilitated studies linking Aβ, cognition, and dementia in DS. However, there are no studies of PiB binding across the lifespan in DS. The current study describes in vitro 3H-PiB binding in the frontal cortex of autopsy cases with DS compared to non-DS controls. Tissue from 64 cases included controls (N=25) and DS (N=39). In DS, 3H-PiB binding was significantly associated with age. After age 40 years in DS, 3H-PiB binding rose dramatically along with increasing individual variability. 3H-PiB binding correlated with the amount of Aβ42. Using fixed frontal tissue and fluorescent 6-CN-PiB, neuritic and cored plaques along with extensive cerebral amyloid angiopathy (CAA) showed 6-CN-PiB binding. These results suggest that cortical PiB binding as shown by positron emission tomography imaging reflects plaques and CAA in DS brain

Cerebrospinal fluid biomarkers of Alzheimer\u27s disease in a cohort of adults with Down syndrome

Introduction: Virtually all individuals with Down syndrome (DS) will develop Alzheimer\u27s disease (AD) pathology by age 40. Cerebrospinal fluid (CSF) biomarkers have characterized AD pathology in cohorts of late-onset AD (LOAD) and autosomal-dominant AD (ADAD). Few studies have evaluated such biomarkers in adults with DS. Methods: CSF concentrations of amyloid beta (Aβ)40, Aβ42, tau, phospho-tau181 (p-tau), neurofilament light chain (NfL), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40), alpha synuclein (αSyn), neurogranin (Ng), synaptosomal-associated protein 25 (SNAP-25), and visinin-like protein 1 (VILIP-1) were assessed in CSF from 44 adults with DS from the Alzheimer\u27s Biomarker Consortium-Down Syndrome study. Biomarker levels were evaluated by cognitive status, age, and apolipoprotein E gene ( Results: Biomarker abnormalities indicative of amyloid deposition, tauopathy, neurodegeneration, synaptic dysfunction, and neuroinflammation were associated with increased cognitive impairment. Age and Discussion: The profile of many established and emerging CSF biomarkers of AD in a cohort of adults with DS was similar to that reported in LOAD and ADAD, while some differences were observed