Prevalence of non-febrile seizures in children with idiopathic autism spectrum disorder and their unaffected siblings: a retrospective cohort study

BACKGROUND: Autism spectrum disorder (ASD) is a heterogeneous disorder characterized not only by deficits in communication and social interactions but also a high rate of co-occurring disorders, including metabolic abnormalities, gastrointestinal and sleep disorders, and seizures. Seizures, when present, interfere with cognitive development and are associated with a higher mortality rate in the ASD population. METHODS: To determine the relative prevalence of non-febrile seizures in children with idiopathic ASD from multiplex and simplex families compared with the unaffected siblings in a cohort of 610 children with idiopathic ASD and their 160 unaffected siblings, participating in the Autism Genetic Resource Exchange project, the secondary analysis was performed comparing the life-time prevalence of non-febrile seizures. Statistical models to account for non-independence of observations, inherent with the data from multiplex families, were used in assessing potential confounding effects of age, gender, and history of febrile seizures on odds of having non-febrile seizures. RESULTS: The life-time prevalence of non-febrile seizures was 8.2% among children with ASD and 2.5% among their unaffected siblings. In a logistic regression analysis that adjusted for familial clustering, children with ASD had 5.27 (95%CI: 1.51–18.35) times higher odds of having non-febrile seizures compared to their unaffected siblings. In this comparison, age, presence of gastrointestinal dysfunction, and history of febrile seizures were significantly associated with the prevalence of non-febrile seizures. CONCLUSION: Children with idiopathic ASD are significantly more likely to have non-febrile seizures than their unaffected siblings, suggesting that non-febrile seizures may be ASD-specific. Further studies are needed to determine modifiable risk factors for non-febrile seizures in ASD

Longitudinal decreases in multiple cerebrospinal fluid biomarkers of neuronal injury in symptomatic late onset Alzheimer\u27s disease

INTRODUCTION: Individuals in early stages of Alzheimer\u27s disease are a targeted population for secondary prevention trials aimed at preserving normal cognition. Understanding within-person biomarker(s) change over time is critical for trial enrollment and design. METHODS: Longitudinal cerebrospinal fluid samples from the Alzheimer\u27s Disease Neuroimaging Initiative were assayed for novel markers of neuronal/synaptic injury (visinin-like protein 1, Ng, and SNAP-25) and neuroinflammation (YKL-40) and compared with β amyloid 42, tau, and phospho-tau181. General linear mixed models were used to compare within-person rates of change in three clinical groups (cognitively normal, mild cognitive impairment, and Alzheimer\u27s disease) further defined by β amyloid status. RESULTS: Levels of injury markers were highly positively correlated. Despite elevated baseline levels as a function of clinical status and amyloid-positivity, within-person decreases in these measures were observed in the early symptomatic, amyloid-positive Alzheimer\u27s disease group. DISCUSSION: Knowledge of within-person biomarker change will impact interpretation of biomarker outcomes in clinical trials that are dependent on disease stage

Lack of association between acute stroke, post-stroke dementia, race, and β-amyloid status

INTRODUCTION: Stroke and Alzheimer disease share risk factors and often co-occur, and both have been reported to have a higher prevalence in African Americans as compared to non-Hispanic whites. However, their interaction has not been established. The objective of this study was to determine if preclinical Alzheimer disease is a risk factor for stroke and post-stroke dementia and whether racial differences moderate this relationship. METHODS: This case-control study was analyzed in 2019 using retrospective data from 2007 to 2013. Participants were adults age 65 and older with and without acute ischemic stroke. Recruitment included word of mouth and referrals in Saint Louis, MO, with stroke participants recruited from acutely hospitalized patients and non-stroke participants from community living older adults who were research volunteers. Our assessment included radiologic reads of infarcts, microbleeds, and white matter hyperintensitites (WMH); a Pittsburgh Compound B PET measure of cortical β-amyloid binding; quantitative measures of hippocampal and WMH volume; longitudinal Mini Mental State Examination (MMSE) scores; and Clinical Dementia Rating (CDR) 1 year post-stroke. RESULTS: A total of 243 participants were enrolled, 81 of which had a recent ischemic stroke. Participants had a mean age of 75, 57% were women, and 52% were African American. Cortical amyloid did not differ significantly by race, stroke status, or CDR post-stroke. There were racial differences in MMSE scores at baseline (mean 26.8 for African Americans, 27.9 for non-Hispanic whites, p = 0.03), but not longitudinally. African Americans were more likely to have microbleeds (32.8% vs 22.6%, p = 0.04), and within the acute stroke group, African Americans were more likely to have small infarcts (75.6% vs 56.8%, p = 0.049). CONCLUSION: Preclinical Alzheimer disease did not show evidence of being a risk factor for stroke nor predictive of post-stroke dementia. We did not observe racial differences in β-amyloid levels. However, even after controlling for several vascular risk factors, African Americans with clinical stroke presentations had greater levels of vascular pathology on MRI

Upward drift in cerebrospinal fluid amyloid β 42 assay values for more than 10 years

Introduction: The best-established cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease are levels of amyloid β 42 (Aβ42), total tau (tau), and phosphorylated tau 181 (ptau). We examined whether a widely used commercial immunoassay for CSF Aβ42, tau, and ptau provided stable measurements for more than ∼10 years. Methods: INNOTEST assay values for CSF Aβ42, tau, and ptau from Washington University in St. Louis and VU Medical Center, Amsterdam, were evaluated. Results: Aβ42 values as measured by the INNOTEST assay drifted upward by approximately 3% per year over the past decade. Tau values remained relatively stable, whereas results for ptau were mixed. Discussion: Assay drift may reduce statistical power or even confound analyses. The drift in INNOTEST Aβ42 values may reduce diagnostic accuracy for Alzheimer's disease in the clinic. We recommend methods to account for assay drift in existing data sets and to reduce assay drift in future studies

Different rates of cognitive decline in autosomal dominant and late-onset Alzheimer disease

As prevention trials advance with autosomal dominant Alzheimer disease (ADAD) participants, understanding the similarities and differences between ADAD and sporadic late-onset AD (LOAD) is critical to determine generalizability of findings between these cohorts. Cognitive trajectories of ADAD mutation carriers (MCs) and autopsy-confirmed LOAD individuals were compared to address this question. Longitudinal rates of change on cognitive measures were compared in ADAD MCs (n = 310) and autopsy-confirmed LOAD participants (n = 163) before and after symptom onset (estimated/observed). LOAD participants declined more rapidly in the presymptomatic (preclinical) period and performed more poorly at symptom onset than ADAD participants on a cognitive composite. After symptom onset, however, the younger ADAD MCs declined more rapidly. The similar but not identical cognitive trajectories (declining but at different rates) for ADAD and LOAD suggest common AD pathologies but with some differences

ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective