Structural Lesions on Kidney Biopsy in Youth-Onset and Adult-Onset Type 2 Diabetes

OBJECTIVE Type 2 diabetes (T2D) is a leading cause of end-stage kidney disease worldwide. Recent studies suggest a more aggressive clinical course of diabetic kidney disease in youth-onset compared with adult-onset T2D. We compared kidney structural lesions in youth- and adult-onset T2D to determine if youth onset was associated with greater early tissue injury. RESEARCH DESIGN AND METHODS Quantitative microscopy was performed on kidney tissue obtained from research kidney biopsies in 161 Pima Indians (117 women, 44 men) with T2D. Onset of T2D was established by serial oral glucose tolerance testing, and participants were stratified as youth onset (age <25 years) or adult onset (age ≥25 years). Associations between clinical and morphometric parameters and age at onset were tested using linear models. RESULTS At biopsy, the 52 participants with youth-onset T2D were younger than the 109 with adult-onset T2D (39.1 ± 9.9 vs. 51.4 ± 10.2 years; P < 0.0001), but their diabetes duration was similar (19.3 ± 8.1 vs. 17.0 ± 7.8 years; P = 0.09). Median urine albumin-to-creatinine ratio was higher in the youth-onset group (58 [25th–75th percentile 17–470] vs. 27 [13–73] mg/g; P = 0.02). Youth-onset participants had greater glomerular basement membrane (GBM) width (552 ± 128 vs. 490 ± 114 nm; P = 0.002) and mesangial fractional volume (0.31 ± 0.10 vs. 0.27 ± 0.08; P = 0.001) than adult-onset participants. Glomerular sclerosis percentage, glomerular volume, mesangial fractional volume, and GBM width were also inversely associated with age at diabetes onset as a continuous variable. CONCLUSIONS Younger age at T2D onset strongly associates with more severe kidney structural lesions. Studies are underway to elucidate the pathways underlying these associations.

A Comparison of IgG Index and Oligoclonal Band in the Cerebrospinal Fluid for Differentiating between RRMS and NMOSD

As the oligoclonal band in the cerebrospinal fluid (CSF-OCB) in predicting relapsing-remitting multiple sclerosis (RRMS) is less sensitive in Asian populations than that in westerners, it remains elusive whether the IgG index could serve as an alternative. The purpose of this study was to compare these two methods of differentiating between RRMS and neuromyelitis optica spectrum disorder (NMOSD) in Chinese patients. A total of 171 patients (81 RRMS and 90 NMOSD) were retrospectively recruited, of whom 82 (56 RRMS and 26 NMOSD) received the CSF-OCB testing additionally. When the onset age was ≤38.5 years, IgG index with the threshold of 0.67 had a significant agreement (к = 0.4, p < 0.001) with the diagnosis while CSF-OCB failed to discriminate (к = 0.1, p = 0.578). However, when the onset age was >38.5 years, both IgG index with the threshold of 0.8 and CSF-OCB were moderately consistent with the diagnosis (both к > 0.4, p < 0.05). In total, our optimized algorithm had the sensitivity, specificity, and predictive accuracy of 0.778, slightly outperforming the CSF-OCB model. Accordingly, a combination of the onset age and IgG index could serve as an alternative to CSF-OCB for differentiating between RRMS and NMOSD in Chinese patients.

Age of Symptom Onset and Longitudinal Course of Sporadic Alzheimer’s Disease, Frontotemporal Dementia, and Vascular Dementia: A Systematic Review and Meta-Analysis

Background: Understanding how the age of dementia symptom onset affects the longitudinal course of dementia can assist with prognosis and care planning. Objective: To synthesize evidence regarding the relationship of age of symptom onset with the longitudinal course of sporadic Alzheimer’s disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD). Methods: We searched Medline, CINAHL, Embase, PsycINFO, PubMed, and Scopus for longitudinal studies that examined the impact of sporadic AD, VaD, or FTD symptom onset age on measures of cognition, function, or behavioral symptoms. Studies that examined age at diagnosis only were excluded. Quantitative meta-analysis was conducted where studies reported sufficient data for pooling. Results: Thirty studies met all inclusion criteria (people with AD (n = 26), FTD (n = 4)) though no studies examined VaD. Earlier onset of AD was associated with more rapid annual cognitive decline (estimate = –0.07; 95% CI –0.14 to 0.00; p = 0.045). Most studies that stratified their sample reported that younger AD onset (usually < 65 years) was associated with more rapid cognitive decline. Other evidence was inconclusive. Conclusion: Younger people with AD appear to have a poorer prognosis in terms of faster cognitive decline than older people with AD. More research is required to determine the impact of symptom onset age in VaD and FTD, and on functional decline in all dementias.

Clinical and Therapeutic Characteristics of Pituitary TSH-Secreting Adenoma in Adolescent-Onset Patients: Six Case Studies and Literature Review

BackgroundThyrotropin-secreting adenoma (TSH-oma) is a very rare kind of functional pituitary adenoma, especially that which occurs in adolescents. However, its potential clinical and therapeutic characteristics are still unknown.ObjectivesThe study was aimed to summarize the clinical and therapeutic characteristics of patients with adolescent-onset TSH-oma.MethodsWe retrospectively analyzed six (4.1%) adolescent-onset TSH-oma cases from 148 patients who were diagnosed with TSH-oma at our hospital between January 2012 and October 2020. A literature review was performed on the PubMed online database, and 14 adolescent-onset TSH-oma cases were retrieved. Then, the characteristics of clinical manifestations, treatment outcomes, and follow-ups were analyzed and compared to the adult TSH-oma patients.ResultsAltogether, 20 adolescent-onset cases were included in this study having mean onset age of 13.4 ± 3.3 years. Males were found to be slightly predominant (M: F = 1.5:1) in our study. The median baseline levels of TSH, FT3, and FT4 in adolescent-onset cases were found to be 6.30 [interquartile range (IQR) 9.82] µIU/ml, 9.18 (IQR 11.61) pg/ml, and 3.22 (IQR 1.90) ng/dl, respectively, which were all significantly higher than the adult patients of our hospital. Also, the adolescent-onset cases showed more large tumor ratio (36.8% vs. 9.3%, p = 0.007) compared to the adult patients. Compared to the patients of all ages in the literature, the biochemical remission rate of SSAs (57.1%) and remission rate of TSS (38.9%) were found to be considerably lower in adolescent-onset patients, while the recurrence rate (44.4%) was found to be considerably higher.ConclusionsAdolescent-onset TSH-oma patients showed higher TSH and thyroid hormone levels, more large tumors, and worse treatment outcomes than adult cases. Hence, early diagnosis, multidisciplinary therapy, and close follow-up should be highlighted to improve the prognosis.

Clinical characteristics and risk factors for survival in affected offspring of von Hippel-Lindau disease patients

BackgroundVon Hippel-Lindau (VHL) disease is an autosomal dominant genetic tumour syndrome with poor prognosis. The clinical manifestation was found to be more serious in affected offspring of patients with VHL disease, but the risk factors and survival for them have never been reported before. We aimed to explore how these patients were influenced by genetic and clinical factors.MethodsIn this retrospective study, we collected 372 affected offspring of VHL patients from 118 unrelated VHL families. Patients were stratified into different groups based on sets of variables. The age-related risk, overall survival and central nervous systemhaemangioblastoma (CHB)-specific survival were analysed between different groups using Kaplan-Meier survival analysis and Cox regression analysis.ResultsThe estimated median life expectancy and median age of onset for affected offspring of VHL patients were 66 years and 28 years, respectively. The later generation and patients with mutations in exon 3 had an earlier onset age. The first presenting symptom was the only independent risk factor influencing overall survival and CHB-specific survival. Patients that the first presenting symptom is central nervous system (CNS) significantly had a lower life expectancy both in overall survival and CHB-specific survival analysis than abdominal lesions group.ConclusionThis study indicated that affected offspring of VHL patients with CNS as the first presenting symptom was an independent risk factor for overall survival and CHB-specific survival. Generation and mutation region only had an effect on the onset age, which is helpful to clinical decision-making and generate a more precise surveillance protocol.

Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts

Alzheimer’s disease biomarkers are becoming increasingly important for characterizing the longitudinal course of disease, predicting the timing of clinical and cognitive symptoms, and for recruitment and treatment monitoring in clinical trials. In this work, we develop and evaluate three methods for modeling the longitudinal course of amyloid accumulation in three cohorts using amyloid PET imaging. We then use these novel approaches to investigate factors that influence the timing of amyloid onset and the timing from amyloid onset to impairment onset in the Alzheimer’s disease continuum.Data were acquired from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Baltimore Longitudinal Study of Aging (BLSA) and the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Amyloid PET was used to assess global amyloid burden. Three methods were evaluated for modeling amyloid accumulation using 10-fold cross-validation and hold-out validation where applicable. Estimated amyloid onset age was compared across all three modeling methods and cohorts. Cox regression and accelerated failure time models were used to investigate whether sex, apolipoprotein E genotype and e4 carriage were associated with amyloid onset age in all cohorts. Cox regression was used to investigate whether apolipoprotein E (e4 carriage and e3e3, e3e4, e4e4 genotypes), sex or age of amyloid onset were associated with the time from amyloid onset to impairment onset (global Clinical Dementia Rating ≥1) in a subset of 595 ADNI participants that were not impaired prior to amyloid onset.Model prediction and estimated amyloid onset age were similar across all three amyloid modeling methods. Sex and apolipoprotein E-e4 carriage were not associated with PET-measured amyloid accumulation rates. Apolipoprotein E genotype and e4 carriage, but not sex, were associated with amyloid onset age such that e4 carriers became amyloid positive at an earlier age compared to non-carriers, and greater e4 dosage was associated with an earlier amyloid onset age. In the ADNI, e4 carriage, being female and a later amyloid onset age were all associated with a shorter time from amyloid onset to impairment onset. The risk of impairment onset due to age of amyloid onset was nonlinear and accelerated for amyloid onset age >65. These findings demonstrate the feasibility of modeling longitudinal amyloid accumulation to enable individualized estimates of amyloid onset age from amyloid PET imaging. These estimates provide a more direct way to investigate the role of amyloid and other factors that influence the timing of clinical impairment in Alzheimer’s disease.

Bilingualism and Healthy Aging: Onset Age of Bilingualism as a Predictor of Older Adult Theory of Mind

The ability to understand and speak more than one language (i.e., bilingualism) may protect against age-related cognitive deterioration (Abutalebi et al., 2015). While there is mounting evidence suggesting that bilingualism confers advantages in domain-general cognitive abilities in late adulthood (see Bialystok, 2017, for a review), few studies have investigated the influences of bilingualism on socio-cognitive abilities such as theory of mind (ToM) in the normal aging process. Thus, in this study, we examine how bilingualism factors (i.e., onset age of bilingualism, language balance, and diversity in language use) are associated with individual differences in ToM in healthy older adult bilinguals aged 58-79 (N=44). ToM abilities were assessed using the Theory-of-Mind Task Battery (Hutchins et al., 2008), where participants viewed vignettes and answered questions about the protagonists’ cognitive and affective mental states. All participants completed a self-report language background questionnaire and the Montreal Cognitive Assessment (MoCA) test as a measure of general cognitive ability. Results revealed that better ToM was negatively correlated with participants’ chronological age (r=-.43, p=.004) and the onset age of second-language acquisition (r=-.41, p=.006), but not language balance and diversity (ps&gt;.40). Partial regression analyses showed that earlier onset age of bilingualism predicted better ToM performance (β=-.40, p=.009), even after controlling for age, education, and general cognitive ability. These findings suggest that bilingual language experience, particularly earlier exposure to a second language, may provide benefits to older adults in preserving their ability to understand others’ mental states, acting as a cognitive reserve against age-related declines in socio-cognitive functions.

Importance of Early Genetic Sequencing in Neonates Admitted to NICU with Recurrent Hypernatremia: Results of a Prospective Cohort Study

<b><i>Objectives:</i></b> The genetic characteristics in neonates admitted to the NICU with recurrent hypernatremia remained unknown. We aimed to implement early genetic sequencing to identify possible genetic etiologies, optimize the treatment, and improve the outcome. <b><i>Methods:</i></b> We prospectively performed exome sequencing or targeted panel sequencing on neonates diagnosed with recurrent hypernatremia (plasma sodium ≥150 mEq/L, ≥2 episodes) from January 1, 2016, to June 30, 2020. <b><i>Results:</i></b> Among 22,375 neonates admitted to the NICU, approximately 0.33% (73/22,375) developed hypernatremia. The incidence of hypernatremia &#x3e;14 days and ≤14 days was 0.03% and 0.3%, respectively. Among 38 neonates who had ≥2 hypernatremia episodes, parents of 28 patients consented for sequencing. Genetic diagnosis was achieved in 25% neonates (7/28). Precision medicine treatment was performed in 85.7% (6/7) of the patients, including hydrochlorothiazide and indomethacin for 57.1% (4/7) with arginine vasopressin receptor 2 (<i>AVPR2</i>) deficiency-associated congenital nephrogenic diabetes insipidus; a special diet of fructose formula for 1 patient with solute carrier family 5 member 1 deficiency-associated congenital glucose-galactose malabsorption (1/7, 14.3%); and kallikrein-inhibiting ointment for 1 patient with serine protease inhibitor of Kazal-type <i>5</i> deficiency-associated Netherton syndrome (1/7, 14.3%). Only hypernatremia onset age (adjusted odds ratio 1.32 [1.01–1.72], <i>p</i> = 0.040) independently predicted the underlying genetic etiology. The risk of a genetic etiology of hypernatremia was 9.0 times higher for neonates with a hypernatremia onset age ≥17.5 days (95% confidence interval, 1.1–73.2; <i>p</i> = 0.038). <b><i>Conclusions:</i></b> Single-gene disorders are common in neonates with recurrent hypernatremia, and &#x3e;50% of cases are caused by <i>AVPR2</i> deficiency-associated congenital nephrogenic diabetes insipidus. Early genetic testing can aid the diagnosis of unexplained recurrent neonatal hypernatremia and improve therapy and outcome.