MaineGeneral Medical Center

We conducted the PediQUEST Response to the Pediatric Oncology Symptom Experience (PQ Response) randomized controlled trial (RCT) to assess whether combining feedback from an electronic patient-reported outcome (ePRO) system with specialized pediatric palliative care (SPPC) consultation improved health-related quality of life (HRQOL) in children with advanced cancer. This multicenter open-label RCT enrolled children 2 years and older with advanced cancer. The study was conducted between April 2018 and December 2021 at five US tertiary-level pediatric cancer centers. All parents and children 5 years and older answered weekly child HRQOL and symptom surveys over 18 weeks (2-week run-in). Child-parent dyads were assigned (1:1) to PQ Response (n = 74) or usual care (n = 80) for 16 weeks. Primary outcomes were the difference between average 16-week and baseline Pediatric Quality of Life Inventory (PedsQL-4.0) total scores reported by parents and children (range, 0-100; higher = better HRQOL; minimal clinically important difference [MCID], 4.5). Secondary outcomes were PedsQL subscales and symptom scores. Analyses followed an intention-to-treat approach. Of 154 participants randomly assigned, 50% were girls, 78% were White, 17% were Hispanic, and 45% had brain tumors. The mean age was 11 years (standard deviation, 6.1). Parents assigned to PQ Response reported greater improvements in child HRQOL (PedsQL total mean difference 3.45 points [{95% CI, 0.48 to 6.43}; P = .023]; PedsQL physical 4.61 [{95% CI, 0.40 to 8.82}; P = .032]). Children reported similar improvements. Effects did not exceed MCIDs. No improvements were observed in PedsQL-psychosocial or symptom scores. Sensitivity analyses showed consistent effects, with most physical HRQOL scores and several child-reported symptom scores exceeding MCIDs. We observed site-specific variability. At the site with the largest adherence, all effects exceeded MCIDs. No adverse events reported. Findings suggest benefits of integrating electronic patient-reported outcome feedback and SPPC into pediatric advanced cancer care. Enhanced implementation strategies are needed to optimize clinical impact.

BackgroundNeuropsychiatric symptoms (NPS) are common in the preclinical and prodromal stages of Alzheimer's Disease and Related Dementias (ADRD) and are associated with cognitive and functional decline. However, the neurobiology of these symptoms and prognostic markers of their emergence are not well understood. We sought to examine the associations between established baseline plasma biomarkers of ADRD and the longitudinal trajectory of NPS in older adults.MethodParticipants were from the Massachusetts Alzheimer's Disease Research Center longitudinal research cohort. A subset, spanning consensus diagnoses of cognitively normal (CN)(n = 282, age:68±10) years) to mild cognitive impairment (MCI)(n = 331, age:74±8 years), had baseline plasma samples assayed for phospho‐tau217 (p‐tau217), neurofilament‐light (NfL) and glial fibrillary acidic protein (GFAP) (Table 1). Average follow‐up was 8.6±4.2 years (CN) and 7.2±4.1 years (MCI). NPS were measured annually using the self‐reported Geriatric Depression Scale (GDS‐15) and the study‐partner‐reported Neuropsychiatric Inventory Questionnaire (NPI‐Q). Plasma biomarkers were log‐transformed and z‐scores were derived using baseline values of the study sample. In longitudinal linear mixed‐effects models, we examined the NPS measures as the dependent variable in relation to individual plasma biomarkers, time, and the plasma biomarker × time interaction, controlling for age and sex.ResultIn CN participants, plasma NfL and GFAP were associated with change in GDS (NfL x time: β=0.02, CI=0.01‐0.03 p = 0.007); GFAP x time: β=0.02, CI=0.01‐0.04, p = 0.002) but not with NPI‐Q (p >0.05 for all); (Figure 1). In MCI participants, p‐tau217 and NfL were associated with change in GDS (p‐tau217: β=0.02, CI=0‐0.04, p = 0.04; NfL: β=0.02, CI=0‐0.04, p = 0.02) whereas all three biomarkers predicted increasing NPI‐Q score over time (p‐tau217: β=0.09 CI=0.07‐0.12, p <0.001; NfL: β=0.03, CI=0‐0.06 p = 0.025; GFAP: β=0.07, CI=0.04‐0.10, p <0.001) (Figure 2). In exploratory NPI‐Q analyses, when NfL and GFAP were individually added as predictors alongside p‐tau217, only p‐tau217 remained significant.ConclusionFindings suggest differential plasma biomarker‐NPS associations across the early ADRD spectrum, with a central role of p‐tau217 at the stage of MCI. Results also support biomarker signatures of affective vs. overall NPS. Further dissecting plasma biomarker signatures of specific NPS domains will provide insight into the prognostic value of plasma measures in predicting NPS trajectories over the course of ADRD.

The amyloid precursor protein (APP) is cleaved by β- and γ-secretases, resulting in the generation of β-amyloid (Aβ). Aβ peptides accumulate in the brain of Alzheimer’s disease, and the removal of toxic Aβ species using antibodies slows the progression of the disease. However, the potential physiological function(s) of APP and its family members remains elusive. Various studies, including ours, reported that APP C99 is primarily processed by γ-secretase in the endo-lysosomal compartments. Here, we report using a series of complementary assays that the endo-lysosomal membrane in APP/amyloid precursor–like protein 2 (APLP2) deficient mouse embryonic fibroblast cells is more vulnerable to leakage caused by oxidative stress, adeno-associated virus, or tau incubation, compared with that in WT controls. The increased vulnerability of the endo-lysosomal membrane is, in part, rescued by APP overexpression, suggesting the contribution of both APP and APLP2. Mechanistically, we observed distinct lipid profiles, including increased cholesterol and Hex1Cer, between the membrane of APP/APLP2 dKO and that of WT mouse embryonic fibroblast cells. Furthermore, we uncovered higher APP expression in primary neurons from the cerebellum of mouse embryos compared with those from the cortex, and the endo-lysosomal membrane in the cerebellum neurons is less vulnerable to leakage than that in the cortical neurons. Taken together, our findings suggest an unrecognized role of APP and its family member in the regulation of endo-lysosomal membrane vulnerability.

Neuronal loss is the ultimate driver of neural system dysfunction in Alzheimer's disease (AD). We used single-nucleus RNA sequencing and neuropathological phenotyping to elucidate mechanisms of neurodegeneration in AD by identifying vulnerable neuronal populations and probing for their differentially expressed genes. Evidenced by transcriptomic analyses and quantitative tau immunoassays of human AD and non-AD brain tissue, we identified a neuronal population especially vulnerable to tau pathology. Multiplexed immunohistochemistry and in situ hybridization (CBLN2 and LINC00507) validated the presence of the tau-vulnerable neuronal population and revealed a propensity of this population to bear tau pathology. Differentially expressed genes associated with phospho-tau pathology in these neurons revealed genes involved in apoptosis, cell-component dissociation (e.g., autophagosome maturation and actin filament depolymerization), and regulation of vesicle-mediated transport.

Felix is a boy aged 10years with autism and attention-deficit/hyperactivity disorder who presents to the pediatric emergency department for acute behavior change, including decreased interactivity, decreased speech, bruxism, and new urinary incontinence. He is admitted during the weekend, and scheduling of magnetic resonance imaging is delayed. Eventually, he has a computed tomography scan of his head, which shows an abnormal diffuse hypodensity involving the frontal lobe with extension into the cortex, all concerning for ischemia, and he is ultimately diagnosed with Moyamoya disease complicated by stroke. Felix and his family self-identify as Latino and Black and prefer to use a language other than English for medical discussions. Through this case, we (1) reflect on the barriers to clinical care faced by patients with autism; (2) define intersectionality and explore how neurodivergence, race, ethnicity, and parental-provider language discordance can augment and inhibit the provision of equitable care; and (3) discuss strategies that may mitigate the impact of oppression on clinical care.

Missense mutations in the amyloid precursor protein (APP) and presenilin-1 (PSEN1) cause early-onset familial Alzheimer's disease (FAD) and alter proteolytic production of secreted 38-to-43-residue amyloid β-peptides (Aβ) by the PSEN1-containing γ-secretase complex, ostensibly supporting the amyloid hypothesis of pathogenesis. However, proteolysis of APP substrate by γ-secretase is processive, involving initial endoproteolysis to produce long Aβ peptides of 48 or 49 residues followed by carboxypeptidase trimming in mostly tripeptide increments. We recently reported evidence that FAD mutations in APP and PSEN1 cause deficiencies in early steps in processive proteolysis of APP substrate C99 and that this results from stalled γ-secretase enzyme-substrate and/or enzyme-intermediate complexes. These stalled complexes triggered synaptic degeneration in a Caenorhabditis elegans model of FAD independently of Aβ production. Here, we conducted full quantitative analysis of all proteolytic events on APP substrate by γ-secretase with six additional PSEN1 FAD mutations and found that all six are deficient in multiple processing steps. However, only one of these (F386S) was deficient in certain trimming steps but not in endoproteolysis. Fluorescence lifetime imaging microscopy in intact cells revealed that all six PSEN1 FAD mutations lead to stalled γ-secretase enzyme-substrate/intermediate complexes. The F386S mutation, however, does so only in Aβ-rich regions of the cells, not in C99-rich regions, consistent with the deficiencies of this mutant enzyme only in trimming of Aβ intermediates. These findings provide further evidence that FAD mutations lead to stalled and stabilized γ-secretase enzyme-substrate and/or enzyme-intermediate complexes and are consistent with the stalled process rather than the products of γ-secretase proteolysis as the pathogenic trigger.

White matter hyperintensities (WMHs) are frequently observed on magnetic resonance imaging (MRI) in patients with cerebral amyloid angiopathy (CAA). The neuropathological substrates that underlie WMHs in CAA are unclear, and it remains largely unexplored whether the different WMH distribution patterns associated with CAA (posterior confluent and subcortical multispot) reflect alternative pathophysiological mechanisms. We performed a combined invivo MRI-ex vivo MRI-neuropathological study in patients with definite CAA. Formalin-fixed hemispheres from 19 patients with CAA, most of whom also had invivo MRI available, underwent 3T MRI, followed by standard neuropathological examination of the hemispheres and targeted neuropathological assessment of WMH patterns. Exvivo WMH volume was independently associated with CAA severity (P=0.046) but not with arteriolosclerosis (P=0.743). In targeted neuropathological examination, compared with normal-appearing white matter, posterior confluent WMHs were associated with activated microglia (P=0.043) and clasmatodendrosis (P=0.031), a form of astrocytic injury. Trends were found for an association with white matter rarefaction (P=0.074) and arteriolosclerosis (P=0.094). An exploratory descriptive analysis suggested that the histopathological correlates of WMH multispots were similar to those underlying posterior confluent WMHs. This study confirmed that vascular amyloid β severity in the cortex is significantly associated with WMH volume in patients with definite CAA. The histopathological substrates of both posterior confluent and WMH multispots were comparable, suggesting overlapping pathophysiological mechanisms, although these exploratory observations require confirmation in larger studies.