Discovery and validation of dominantly inherited Alzheimer\u27s disease mutations in populations from Latin America

BACKGROUND: In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations. METHODS: Clinical data was collected from LatAm families at risk for DIAD. Symptomatic family members were identified and assessed by local clinicians and referred for genetic counseling and testing. To determine the likelihood of pathogenicity among variants of unknown significance from LatAm populations, we report pedigree information, frequency in control populations, in silico predictions, and cell-based models of amyloid-beta ratios. RESULTS: We identified five novel variants in the presenilin1 (PSEN1) gene from Brazilian and Mexican families. The mean age at onset in newly identified families was 43.5 years (range 36-54). PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr, and p.Ile414Thr variants have not been reported in PubMed, ClinVar, and have not been reported in dominantly inherited AD (DIAD) families. We found that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr produce Aβ profiles consistent with known AD pathogenic mutations. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation. CONCLUSIONS: Our study provides further insights into the genetics of AD in LatAm. Based on our findings, including clinical presentation, imaging, genetic, segregations studies, and cell-based analysis, we propose that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr are likely pathogenic variants resulting in DIAD, whereas PSEN1 p.Ile414Thr is likely a risk factor. This report is a step forward to improving the inclusion/engagement of LatAm families in research. Family discovery is of great relevance for the region, as new initiatives are underway to extend clinical trials and observational studies to families living with DIAD

The Effect of Pet Therapy and Artist Interactions on Quality of Life in Brain Tumor Patients: A Cross-Section of Art and Medicine in Dialog

With the evolution of modern medical treatment strategies, there also comes the realization that many times we reach a point where traditional goals of medical care, such as overall survival or disease-free survival, are not realistic goals for many patients facing devastating illnesses. One such disease is malignant primary brain tumors, known as malignant glioma (MG). With median survival of only 20.9 months following best available standard of care treatment strategies, including surgery, chemotherapy, radiation, and tumor treating fields, MG is one of the deadliest malignancies of the modern era. Along the course of treating patients with MG, clinicians often realize that traditional treatment therapies can at best provide incremental benefit of symptom management without any survival benefit. However, even in these difficult situations, it is possible to make significant positive changes in patients’ health-related quality of life (HRQoL) using creative, non-traditional interventions. In this paper, we describe the initial findings from our project that takes a unique approach to studying the intersections of clinical care and art by using pet therapy and art-making as interventions for patients diagnosed with brain tumors. Our preliminary findings suggest that pet therapy and the ability to reflect as well as speak about their journey through a life-altering disease significantly increases patients’ overall feeling of wellbeing and reduces anxiety about future uncertainty