👤 Jeff A Kingsley

The prognostic value of jointly assessing lipoprotein(a) [Lp(a)] and high-sensitivity C-reactive protein (hsCRP) in primary prevention among individuals without standard modifiable risk factors (SMuRFs) remains unclear. We analyzed 50,450 UK Biobank participants free of cardiovascular disease at baseline who were SMuRF-less, defined as absence of current smoking, obesity, hypertension, dyslipidemia, and diabetes. Elevated Lp(a) and hsCRP were defined using cohort-specific 75th percentile cutoffs and established clinical thresholds. Incident atherosclerotic cardiovascular disease (ASCVD), defined as nonfatal myocardial infarction, nonfatal ischemic stroke, or cardiovascular death, was ascertained. Associations were evaluated using Fine-Gray competing-risk regression models to estimate subdistribution hazard ratios (sHRs) with 95% confidence intervals (CI), accounting for competing non-cardiovascular death. Over 15 years of follow-up, 1,104 (2.2%) incident ASCVD events occurred. Using cohort-specific cutoffs, elevated hsCRP was associated with higher ASCVD risk (sHR 1.35, 95% CI 1.16-1.57), while elevated Lp(a) showed a more modest association (sHR 1.24, 95% CI 1.06-1.45). In joint analyses, isolated elevations of hsCRP or Lp(a) were each associated with increased risk, with the highest risk observed among individuals with concurrent elevations (sHR 1.64, 95% CI 1.28-2.09), without evidence of interaction. Similar patterns were observed using clinical cutoffs (Lp(a) ≥125 nmol/L; hsCRP ≥2.0 mg/L), with concurrent elevation conferring the greatest risk (sHR 1.74, 95% CI 1.17-2.59). In SMuRF-less individuals, Lp(a) and hsCRP independently predict ASCVD risk. These findings suggest that combined assessment of Lp(a) and hsCRP may provide complementary information for risk characterization among SMuRF-less adults in primary prevention. Show less

Insulin resistance (IR) and lipoprotein(a), Lp(a), are established contributors to cardiovascular disease (CVD) risk. Whether IR modifies the association between Lp(a) and CVD in primary prevention remains uncertain. This prospective cohort study included UK Biobank participants without baseline CVD. IR at enrollment was assessed using the triglyceride-glucose index (TyG). The primary outcome was first major adverse cardiovascular event, defined as peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, or cardiovascular death. Cox models estimated adjusted hazard ratios (aHRs) with 95% CIs for log-transformed Lp(a) and TyG, adjusting for each other. Lp(a) was categorized as <125 or ≥125 nmol/L; high IR was TyG ≥75th cohort percentile. Participants were stratified into 4 joint Lp(a)/IR groups using low Lp(a)/low IR as reference. Among 328 031 participants (mean age 56.4 years; 54.7% women), 26 865 CVD events occurred over 14.6 years median follow-up (interquartile range 13.7-15.4). Per 1-SD increase, aHRs were 1.08 (95% CI, 1.06-1.09) for log-Lp(a) and 1.06 (95% CI, 1.04-1.07) for TyG, each adjusted for the other. The Lp(a) and IR each independently contribute to cardiovascular risk, with a combination offering improved risk stratification. This suggests that accounting for IR may enhance the assessment of Lp(a)-associated risk in the context of primary CVD prevention setting. Show less

Juvenile neuronal ceroid lipofuscinosis (JNCL) is an autosomal recessive disorder of childhood caused by mutations in CLN3. Although visual deterioration is typically the first clinical sign to manifest in affected children, loss of Cln3 in a mouse model of JNCL does not recapitulate this retinal deterioration. This suggests that either the loss of CLN3 does not directly affect retinal cell survival or that nuclei involved in visual processing are affected prior to retinal degeneration. Having previously demonstrated that Cln3(-/-) mice have decreased optic nerve axonal density, we now demonstrate a decrease in nerve conduction. Examination of retino-recipient regions revealed a decreased number of neurons within the dorsal lateral geniculate nucleus (LGNd). We demonstrate decreased transport of amino acids from the retina to the LGN, suggesting an impediment in communication between the retina and projection nuclei. This study defines a novel path of degeneration within the LGNd, providing a mechanism for causation of JNCL visual deficits. Show less

Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten Disease) is one of the most common progressive neurodegenerative disorders of childhood, resulting from autosomal recessive inheritance of mutations in the CLN3 gene. Pathologically, Batten disease is characterized by lysosomal storage of autofluorescent material in all tissue types. Although characterized by seizures, mental retardation, and loss of motor skills, the first presenting symptom of Batten disease is vision loss. High-density oligonucleotide arrays were used to profile approximately 19,000 mRNAs in the eye of 10-week-old Cln3-knockout and normal mice, and the data were compared with that for the cerebellum in the same model as a means to identify gene expression changes that are specific to the eye. A detailed list was compiled of 285 functionally categorized genes that have altered expression in the eye of Cln3-knockout mice before the appearance of the characteristic lysosomal storage material. Furthermore, 18 genes were identified and 6 validated by semiquantitative RT-PCR that have altered expression in the eye, but not in the cerebellum of Cln3-knockout mice. The genes that have altered expression specific to the eye of the Cln3-knockout mouse may be of importance in understanding the function of CLN3 in different tissues. Downregulation of genes associated with energy production in the mitochondria appears to be specific to the eye. The CLN3 defect may result in altered mitochondrial function in eye but not other tissue. More detailed experimentation is needed to understand the contribution of these changes in expression to disease state, and whether these changes are specific for certain cell types within the eye. Show less