Longitudinal cerebrospinal fluid measurements show glial hypo- and hyperactivation in predementia Alzheimer’s disease

Background Brain innate immune activation is associated with Alzheimer’s disease (AD), but degrees of activation may vary between disease stages. Thus, brain innate immune activation must be assessed in longitudinal clinical studies that include biomarker negative healthy controls and cases with established AD pathology. Here, we employ longitudinally sampled cerebrospinal fluid (CSF) core AD, immune activation and glial biomarkers to investigate early (predementia stage) innate immune activation levels and biomarker profiles. Methods We included non-demented cases from a longitudinal observational cohort study, with CSF samples available at baseline (n = 535) and follow-up (n = 213), between 1 and 6 years from baseline (mean 2.8 years). We measured Aβ42/40 ratio, p-tau181, and total-tau to determine Ab (A+), tau-tangle pathology (T+), and neurodegeneration (N+), respectively. We classified individuals into these groups: A−/T−/N−, A+/T−/N−, A+/T+ or N+, or A−/T+ or N+. Using linear and mixed linear regression, we compared levels of CSF sTREM2, YKL-40, clusterin, fractalkine, MCP-1, IL-6, IL-1, IL-18, and IFN-γ both cross-sectionally and longitudinally between groups. A post hoc analysis was also performed to assess biomarker differences between cognitively healthy and impaired individuals in the A+/T+ or N+ group. Results Cross-sectionally, CSF sTREM2, YKL-40, clusterin and fractalkine were higher only in groups with tau pathology, independent of amyloidosis (p < 0.001, A+/T+ or N+ and A−/T+ or N+, compared to A−/T−/N−). No significant group differences were observed for the cytokines CSF MCP-1, IL-6, IL-10, IL18 or IFN-γ. Longitudinally, CSF YKL-40, fractalkine and IFN-γ were all significantly lower in stable A+/T−/N− cases (all p < 0.05). CSF sTREM2, YKL-40, clusterin, fractalkine (p < 0.001) and MCP-1 (p < 0.05) were all higher in T or N+, with or without amyloidosis at baseline, but remained stable over time. High CSF sTREM2 was associated with preserved cognitive function within the A+/T+ or N+ group, relative to the cognitively impaired with the same A/T/N biomarker profile (p < 0.01). Conclusions Immune hypoactivation and reduced neuron–microglia communication are observed in isolated amyloidosis while activation and increased fractalkine accompanies tau pathology in predementia AD. Glial hypo- and hyperactivation through the predementia AD continuum suggests altered glial interaction with Ab and tau pathology, and may necessitate differential treatments, depending on the stage and patient-specific activation patterns.publishedVersio

Fetal size in the second trimester is associated with the duration of pregnancy, small fetuses having longer pregnancies

ABSTRACT: BACKGROUND: Conventionally, the pregnancy duration is accepted to be 280-282 days. Fetuses determined by ultrasound biometry to be small in early pregnancy, have an increased risk of premature birth. We speculate that the higher rate of preterm delivery in such small fetuses represents a pathological outcome not applicable to physiological pregnancies. Here we test the hypothesis that in low-risk pregnancies fetal growth (expressed by fetal size in the second trimester) is itself a determinant for pregnancy duration with the slower growing fetuses having a longer pregnancy. METHODS: We analysed duration of gestation data for 541 women who had a spontaneous delivery having previously been recruited to a cross-sectional study of 650 low-risk pregnancies. All had a regular menses and a known date of their last menstrual period (LMP). Subjects were examined using ultrasound to determine fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) at 10-24 weeks of gestation. Length of the pregnancy was calculated from LMP, and birth weights were noted. The effect of fetal size at 10-24 weeks of gestation on pregnancy duration was assessed also when adjusting for the difference between LMP and ultrasound based fetal age. RESULTS: Small fetuses (z-score -2.5) at second trimester ultrasound scan had lower birth weights (p&lt;0.0001) and longer duration of pregnancy (p&lt;0.0001) than large fetuses (z-score +2.5): 289.6 days (95%CI 288.0 to 291.1) vs. 276.1 (95%CI 273.6 to 278.4) for HC, 289.0 days (95%CI 287.4 to 290.6) vs. 276.9 days (95%CI 274.4 to 279.2) for AC and 288.3 vs. 277.9 days (95%CI 275.6 to 280.1) for FL. Controlling for the difference between LMP and ultrasound dating (using HC measurement), the effect of fetal size on pregnancy length was reduced to half but was still present for AC and FL (comparing z-score -2.5 with +2.5, 286.6 vs. 280.2 days, p=0.004, and 286.0 vs. 280.9, p=0.008, respectively). CONCLUSIONS: Fetal size in the second trimester is a determinant of birth weight and pregnancy duration, small fetuses having lower birth weights and longer pregnancies (up to 13 days compared with large fetuses). Our results support a concept of individually assigned pregnancy duration according to growth rates rather than imposing a standard of 280-282 days on all pregnancie

Early childhood development when second-trimester ultrasound dating disagrees with last menstrual period: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>When an ultrasound-based estimate of gestational age (GA) is less (greater) than an estimate based on a definite last menstrual period, the fetus may grow slower (faster) than average. While the association between these discrepancies in GA estimates and adverse perinatal outcomes has been examined extensively, there is scant evidence about long-term effects, such as child neurodevelopment.</p> <p>Methods</p> <p>Using data from a prospective cohort study titled, NICHD Study of Successive Small-for-Gestational Age Births, we examined if GA discrepancies in early second trimester of pregnancy (17 weeks’ gestation) are associated with: (1) impaired motor and mental function at 13 months (measured using Bayley Scales of Infant Development (Bayley)), and (2) impaired cognitive development at five years (assessed by Wechsler Preschool and Primary Scale of Intelligence – Revised Intelligence Quotient (WPPSI-R)) in the infant. The study population consisted of 572 (30% of the overall sample of 1,945) women who presented for prenatal care in Norway and Sweden between 1986 and 1988.</p> <p>Results</p> <p>Our results showed that GA discrepancies in early second trimester are significantly associated with birthweight. We found no significant relationship, however, with the Bayley development scores at 13 months and with the WPPSI-R IQ measures at five years.</p> <p>Conclusions</p> <p>GA discrepancies at 17 weeks’ gestation are not associated child neurodevelopment. These discrepancies do, however, relate to birthweights, providing a basis for detecting fetal growth patterns early in the second trimester of pregnancy. Our study, however, was unable to evaluate the impact of first-trimester discrepancies on impaired neurodevelopment in the infant.</p