The annual rate of change in serial serum neurofilament light chain (NfL) measurements distinguishes certain Alzheimer’s disease patients up to 16 years in advance of when cognitive symptoms would be expected to develop (Nat Med 2019; doi.org/10.1038/s41591-018-0304-3).
These measurements also correlate with brain thinning confirmed by magnetic resonance imaging and eventually might be used to screen for and monitor progression of the disease, according to an international team of researchers in the Dominantly Inherited Alzheimer Network (DIAN).
The investigators’ findings come from an analysis of 405 DIAN participants, 243 of whom carry a rare autosomal-dominant Alzheimer’s disease mutation (APP, PSEN1, or PSEN2), and 162 unaffected relatives. DIAN participants undergo baseline and follow-up evaluations, including diagnostic and cognitive testing. Overall, 196 participants in this analysis returned for at least one visit, and 39 underwent prospective evaluations to determine whether serum NfL levels predicted cognitive decline.
The researchers used a single-molecule array immunoassay that “presumably” detects an antigen that is a “short and stable fragment … of the core domain of NfL,” which makes it “well suited as a blood biomarker for monitoring a slow neurodegenerative process in the brain,” according to the researchers. Unlike other proteins expressed when brain cells die, NfL does not degrade rapidly in the blood and has been linked to brain atrophy and damage, they added.
Age of symptom onset tends to be specific for each mutation, so the investigators were able to estimate years to symptom onset based on the age when symptoms appeared in other individuals with the same mutation.
Although the researchers had both cerebrospinal fluid and serum results for NfL and confirmed a tight association between the two, they focused on the longitudinal serum results because of the “obvious advantage of a non-invasive disease blood biomarker.”
They found that NfL levels were significantly higher at baseline in those with a mutation and elevated more than 6 years before symptoms would have been predicted to arise. Unaffected relatives had lower NfL levels that remained stable over time.
Children of Mothers With Gestational Diabetes Mellitus at Higher Risk for Impaired Glycemia, Lower Insulin Sensitivity
In the latest salvo about the effect of gestational diabetes mellitus (GDM) on the health of pregnant women and their babies, investigators from the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO FUS) report that in comparison with children born to mothers without GDM those born to mothers with untreated GDM were at higher risk of impaired glucose tolerance (IGT) and of lowered insulin sensitivity (Diabetes Care 2019; dc181646). These findings persisted after adjustments for maternal body mass index (BMI) and the children’s obesity.
The original HAPO study demonstrated that glucose levels lower than those used to define diabetes were associated with adverse pregnancy outcomes. HAPO FUS examined whether hyperglycemia below these thresholds in pregnant women spelled adverse glycemia in their offspring.
The 4,160 participants, ages 10-14, all had mothers who during pregnancy underwent 75-g oral glucose tolerance testing (OGTT) at approximately 28 weeks’ gestation with the results blinded to participants and researchers. In addition to height and weight checks participants underwent a 2-hour OGTT, with samples drawn for glucose and C-peptide at baseline (fasting), 30 minutes, 1 hour, and 2 hours.
In all, 10.6% and 9.2% of participants whose mothers had GDM were determined to have IGT and impaired fasting glucose (IFG), respectively, versus 5% and 7.4%, respectively, in those whose mothers did not have GDM.
Unexplained Cardiac Troponin Elevations Should Not Go Unsolved
New findings underscore that unexplained elevated troponin (cTn) levels—measured by either conventional or high-sensitivity assays—are not benign in patients with suspected acute coronary syndrome (ACS) subsequently discharged without a specific diagnosis and should prompt an ongoing investigation to determine the root cause (J Am Coll Cardiol 2019;73:1-9).\
“The term troponinemia, sometimes used to label this scenario, is trivializing and should be avoided,” according to the researchers.
In a retrospective analysis of 48,872 patients in the SWEDEHEART registry, which tracks individuals admitted to Swedish coronary care units or other specialized facilities because of suspected ACS, researchers found that 15.4% experienced a major adverse event (MAE), defined as the composite of all-cause mortality, myocardial infarction, readmission for heart failure, or stroke.
The risk of MAE and of individual MAE components rose with higher tertiles of cTn levels based upon assay-specific values above the 99th percentile. For example, the hazard ratio for MAE rose from 1.25 in cTn tertile 1 (with lowest levels above the 99th percentile) to 1.59 in tertile 3 (with highest levels above the 99th percentile). Similarly, the hazard ratio for all-cause mortality rose from 1.24 in cTn tertile 1 to 2.76 in cTn tertile 3. Overall, about one-third of patients in the highest assay-specific tertile experienced an event.
“Despite a possibly unidentified etiology of myocardial injury, cTn elevation appears to demask myocardial vulnerability that portends to an increased long-term risk,” wrote the investigators.
Based on these findings they recommend that patients with unexplained cTn results undergo careful workups, including retesting cTn to distinguish acute from chronic elevations, using an alternative cTn assay to rule-out pre-analytical factors, and assessing these patients further with echocardiography and coronary imaging.