Practicalities (and real-life experiences) of dementia in adults with Down syndrome.

Adults with down syndrome (DS) have a lifetime dementia risk in excess of 95%, with a median age of onset of 55 years, due to trisomy 21. Co-occurring Alzheimer's disease (AD) has increased morbidity and mortality, and it is now recommended to screen for AD in all adults with DS beginning at 40 years of age. In this manuscript, we present two clinical cases of adults with DS who developed AD summarizing their medical histories, presenting symptoms, path to diagnosis and psychosocial aspects of care collected from retrospective chart review with caregiver consent. These two cases were chosen due to their complexity and interwoven nature of the medical and psychosocial aspects, and highlight the complexity and nuance of caring for patients with DS and AD.

Feasibility and Acceptance of Direct-to-Home Tele-neuropsychology Services during the COVID-19 Pandemic.

OBJECTIVE: Neuropsychological assessment via video conferencing has been proposed during the COVID-19 pandemic. Existing literature has demonstrated feasibility and acceptance of neuropsychological measures administered by videoconference, although few studies have examined feasibility and patient acceptance of TNP visits directly to patients' homes (DTH-TNP). METHODS: We modified a previously published patient satisfaction survey for DTH-TNP and developed a clinician feasibility survey to examine experiences during DTH-TNP. RESULTS: Seventy-two patients (age range: preschool-geriatric) evaluated by DTH-TNP for cognitive problems at an academic medical center responded to voluntary surveys between April 20, 2020, and August 19, 2020, and 100% indicated satisfaction. Fifty-nine percent of patients reported limitations (e.g., technological concern) during the appointment. 134 clinician surveys were collected and indicated that clinicians achieved the goal of their appointment in 90% of encounters. CONCLUSIONS: These qualitative data suggest that patients and clinicians found DTH-TNP to be satisfactory during the COVID-19 pandemic, while also recognizing limitations of the practice. These results are limited in that voluntary surveys are subject to bias. They support the growing body of literature suggesting that DTH-TNP provides a valuable service, though additional research to establish reliability and validity is needed.

Intellectual functioning among case-matched cohorts of children treated with proton or photon radiation for standard-risk medulloblastoma.

BACKGROUND: Proton therapy may reduce cognitive deficits after radiotherapy among brain tumor survivors, although current data are limited to retrospective comparisons between historical cohorts. The authors compared intelligence quotient scores within a case-matched cohort of children with medulloblastoma treated with proton radiation (PRT) or photon radiation (XRT) over the same time period. METHODS: Among 88 consecutive patients with standard-risk medulloblastoma treated with PRT or XRT at 2 institutions from 2000 to 2009, 50 were matched 1:1 (25 with PRT and 25 with XRT) according to age, gender, date of diagnosis, histology, radiation boost, and craniospinal irradiation dose. One-way analyses of variance were performed to compare the Full-Scale Intelligence Quotient (FSIQ) and associated index scores between the 2 cohorts. RESULTS: Neurocognitive data were available for 37 survivors (17 with PRT and 20 with XRT) from the matched cohort. The mean age was 8.5 years (SD, 4.14 years). The median follow-up was 5.3 years (range, 1.0-11.4 years) and 4.6 years (range, 1.1-11.2 years) for the PRT and XRT cohorts, respectively (P = .193). Patients treated with PRT had significantly higher mean FSIQ (99.6 vs 86.2; P = .021), verbal (105.2 vs 88.6; P = .010), and nonverbal scores (103.1 vs 88.9; P = .011) than the XRT-treated cohort. Differences in processing speed (82.9 vs 77.2; P = .331) and working memory (97.0 vs 92.7; P = .388) were not statistically significant. CONCLUSIONS: Radiotherapy-associated cognitive effects appear to be more attenuated after proton therapy. Comprehensive prospective studies are needed to appropriately evaluate the neurocognitive advantages of proton therapy.

Clinical outcomes of pediatric patients with autism spectrum disorder and other neurodevelopmental disorders and intracranial germ cell tumors.

INTRODUCTION: Intracranial germ cell tumors (IGCTs) are rare tumors of the central nervous system with peak incidence around puberty. Given the developmental origins of IGCTs, we investigated the prevalence of neurodevelopmental disorders (NDDs) in patients with IGCTs and characterized outcomes for patients with NDD and IGCTs. METHODS: A retrospective review of medical records was conducted for 111 patients diagnosed with IGCTs between 1998 and 2018 and evaluated at the Massachusetts General Hospital. Kaplan-Meier method and log-rank test was used for survival analyses. Cox regression analyses were performed for parameters associated with progression-free survival (PFS). RESULTS: Median age at IGCT diagnosis was 12.8 years (range: 4.3-21.7) and median follow-up was 6.5 years (range: 0.2-20.5). Eighteen patients were diagnosed with NDDs prior to IGCT diagnosis, including five patients with autism spectrum disorder (ASD). Of the 67 patients with pure germinomas, four (6.0 %) had prior ASD diagnoses. Patients with NDD had significantly inferior PFS in the nongerminomatous germ cell tumor (NGGCT) cohort. On univariate and multivariable analyses, craniospinal irradiation (CSI) was significantly associated with improved PFS in the NGGCT cohort. CONCLUSIONS: Our study found an ASD prevalence in the pure germinoma cohort more than threefold greater than the national prevalence, suggesting an association between ASD and pure germinomas. Furthermore, patients with NDD and NGGCT had worse PFS, possibly due to fewer patients with NDD receiving CSI. Future prospective studies with larger cohorts are needed to examine associations between NDDs and IGCTs, and further characterize outcomes for patients with NDDs and IGCTs.

Evaluation of the National Task Group-Early Detection Screen for Dementia: Sensitivity to 'mild cognitive impairment' in adults with Down syndrome.

BACKGROUND: The accuracy of the National Task Group-Early Detection Screen for Dementia (NTG-EDSD) was evaluated in a sample of 185 adults with Down syndrome (DS), emphasizing 'mild cognitive impairment (MCI-DS)'. METHOD: Knowledgeable informants were interviewed with the NTG-EDSD, and findings were compared to an independent dementia status rating based on consensus review of detailed assessments of cognition, functional abilities and health status (including physician examination). RESULTS: Results indicated that sections of the NTG-EDSD were sensitive to MCI-DS, with one or more concerns within the 'Memory' or 'Language and Communication' domains being most informative. CONCLUSIONS: The NTG-EDSD is a useful tool for evaluating dementia status, including MCI-DS. However, estimates of sensitivity and specificity, even for detecting frank dementia, indicated that NTG-EDSD findings need to be supplemented by additional sources of relevant information to achieve an acceptable level of diagnostic/screening accuracy.

A comparison study assessing neuropsychological outcome of patients with post-operative pediatric cerebellar mutism syndrome and matched controls after proton radiation therapy.

PURPOSE: Post-operative pediatric cerebellar mutism syndrome (CMS), characterized by mutism, ataxia/hypotonia, and emotional lability, can result in long-term deficits following resection of posterior fossa (PF) tumors. This longitudinal study compared neuropsychological outcomes of pediatric patients with post-operative CMS to a matched control patient group without CMS. METHODS: Fifty-eight PF tumor patients received post-surgical proton radiation therapy (PRT) and testing at baseline and at ≥ 1-year post-PRT over a 10-year period. Of these, 18 (31%) had post-operative CMS with baseline and follow-up neuropsychological test data. Those participants were matched to 18 controls by tumor location, age, gender, and handedness; no significant group differences were found at baseline for clinical/demographic variables. Total mean age at baseline was 7.26 years (SD = 4.42); mean follow-up interval was 3.26 years (SD = 2.24). Areas assessed: overall intelligence, expressive and receptive vocabulary, visuomotor integration, fine motor speed, inhibition, emotional control, depression, and anxiety. RESULTS: Patients were 52% male; 86% medulloblastoma/14% ependymoma; 86% craniospinal irradiation/14% focal radiation; and 86% chemotherapy. No group differences were found between most mean baseline scores; expressive vocabulary and fine motor speed were significantly lower in the post-operative CMS group (p < 0.05). Mean change scores revealed no significant differences for the sample; scores were within the normal range except fine motor skills were impaired for both groups. CONCLUSIONS: Longitudinal neuropsychological outcomes for post-operative pediatric CMS patients did not differ significantly from matched controls without this condition. Patients were in the normal range in all areas except fine motor speed, which was impaired for both groups independent of CMS diagnosis.

Quality of life in patients with proton-treated pediatric medulloblastoma: Results of a prospective assessment with 5-year follow-up.

BACKGROUND: To the authors' knowledge, health-related quality of life (HRQOL) outcomes are not well described in patients with medulloblastoma. The use of proton radiotherapy (RT) may translate into an improved HRQOL. In the current study, the authors report long-term HRQOL in patients with proton-treated pediatric medulloblastoma. METHODS: The current study was a prospective cohort HRQOL study of patients with medulloblastoma who were treated with proton RT and enrolled between August 5, 2002, and October 8, 2015. Both child report and parent-proxy report Pediatric Quality of Life Inventory (PedsQL) surveys were collected at baseline during RT and annually thereafter (score range on surveys of 0-100, with higher scores indicating better HRQOL). Patients were dichotomized by clinical/treatment variables and subgroups were compared. Mixed-model analysis was performed to determine the longitudinal trajectory of PedsQL scores. The Student t test was used to compare long-term HRQOL measures with published means from a healthy child population. RESULTS: Survey data were evaluable for 116 patients with a median follow-up of 5 years (range, 1-10.6 years); the median age at the time of diagnosis was 7.6 years (range, 2.1-18.1 years). At baseline, children reported a total core score (TCS) of 65.9, which increased by 1.8 points annually (P<.001); parents reported a TCS of 59.1, which increased by 2.0 points annually. Posterior fossa syndrome adversely affected baseline scores, but these scores significantly improved with time. At the time of last follow-up, children reported a TCS of 76.3, which was 3.3 points lower than that of healthy children (P = .09); parents reported a TCS of 69, which was 11.9 points lower than that of parents of healthy children (P<.001). Increased follow-up time from diagnosis correlated with improved HRQOL scores. CONCLUSIONS: HRQOL scores appear to increase over time after treatment in children treated with proton RT for medulloblastoma but remain lower compared with those of parent-proxy reports as well as published means from a healthy normative sample of children. Additional follow-up may translate into continued improvements in HRQOL. Cancer 2018. © 2018 American Cancer Society.

Left hippocampal dosimetry correlates with visual and verbal memory outcomes in survivors of pediatric brain tumors.

BACKGROUND: Radiotherapy (RT) in the pediatric brain tumor population causes late neurocognitive effects. In the current study, the authors investigated associations between clinical and dosimetric risk factors and memory outcomes in a cohort of patients treated with proton radiotherapy (PRT). METHODS: A total of 70 patients (median age at PRT, 12.1 years [range, 5.0-22.5 years]) who were treated with PRT were identified with baseline and follow-up evaluations of visual and verbal memory (Children's Memory Scale and the third edition of the Wechsler Memory Scale). Whole-brain as well as bilateral hippocampal and temporal lobe contours were delineated for the calculation of dosimetric indices. Multivariate analyses were performed to assess associations of score changes over time with clinical factors and dosimetric indices. RESULTS: The median neurocognitive follow-up was 3.0 years (range, 1.1-11.4 years). For the entire cohort, delayed and immediate verbal memory scaled scores demonstrated small declines. The mean decline for delayed verbal memory scores was 0.6 (P = .01), and that for immediate verbal memory scores was 0.5 (P = .06). Immediate and delayed visual memory scores were not found to change significantly (+0.1 and -0.3, respectively; P>.30). A higher left hippocampal V20GyE (percentage of the volume of a particular anatomical region receiving at least a 20 gray equivalent) was correlated with a score decline in all 4 measures. Female sex was found to be predictive of lower delayed verbal memory follow-up scores (P = .035). CONCLUSIONS: Only delayed verbal memory scores were found to have declined statistically significantly at follow-up after PRT, reflecting some weakness in verbal memory retrieval. Given a correlation of left hippocampal dosimetry and memory outcomes after PRT, left hippocampal-sparing PRT plans may assist patients with pediatric brain tumors in preserving memory-retrieval abilities. Cancer 2018;124:2238-45. © 2018 American Cancer Society.

Executive functioning, academic skills, and quality of life in pediatric patients with brain tumors post-proton radiation therapy.

Radiation therapy (RT) is integral in the treatment of pediatric brain tumors; however, photon RT (XRT) often results in intellectual decline, executive functioning (EF) deficits, academic underachievement/failure, and lower health-related quality of life (HRQoL). Proton RT (PRT) provides more targeted therapy, minimizing damage to the developing brain, yet few studies have examined its neuropsychological effects. This study investigated the role of EF in academic skills and HRQoL in a sample of children treated with PRT. A mediation model was proposed in which academic skills mediated relations between aspects of EF and school-based HRQoL (sHRQoL). Sixty-five children (x̅age = 12.4; 43.9% male) treated with PRT completed follow-up neuropsychological testing as part of routine care. Measures included assessment of intellectual functioning, EF, attention, and academic skills (reading, math, spelling). Parents reported on children's EF and attention problems. sHRQoL was assessed via child self-report. Children who underwent PRT demonstrated relatively intact intelligence, academics, attention, EF, and sHRQoL, but were at risk for reduced processing speed. Poorer working memory and processing speed were related to lower sHRQoL. Better EF and faster processing speed were associated with better academic skills, which were linked to higher sHRQoL. Better working memory was associated with better math performance, which was linked to higher sHRQoL; this relationship did not hold for reading or spelling. Results highlight the importance of EF skills in academic performance and sHRQoL, and the need for routine screening of EF deficits and proactive supports. Supports may include cognitive rehabilitation and in-class accommodations. Overall, results compare favorably to XRT outcomes reported in the literature.

Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study.

BACKGROUND: Compared with traditional photon radiotherapy, proton radiotherapy irradiates less normal tissue and might improve health outcomes associated with photon radiotherapy by reducing toxic effects to normal tissue. We did a trial to assess late complications, acute side-effects, and survival associated with proton radiotherapy in children with medulloblastoma. METHODS: In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients aged 3-21 years who had medulloblastoma. Patients had craniospinal irradiation of 18-36 Gy radiobiological equivalents (GyRBE) delivered at 1·8 GyRBE per fraction followed by a boost dose. The primary outcome was cumulative incidence of ototoxicity at 3 years, graded with the Pediatric Oncology Group ototoxicity scale (0-4), in the intention-to-treat population. Secondary outcomes were neuroendocrine toxic effects and neurocognitive toxic effects, assessed by intention-to-treat. This study is registered at ClinicalTrials.gov, number NCT00105560. FINDINGS: We enrolled 59 patients from May 20, 2003, to Dec 10, 2009: 39 with standard-risk disease, six with intermediate-risk disease, and 14 with high-risk disease. 59 patients received chemotherapy. Median follow-up of survivors was 7·0 years (IQR 5·2-8·6). All patients received the intended doses of proton radiotherapy. The median craniospinal irradiation dose was 23·4 GyRBE (IQR 23·4-27·0) and median boost dose was 54·0 GyRBE (IQR 54·0-54·0). Four (9%) of 45 evaluable patients had grade 3-4 ototoxicity according to Pediatric Oncology Group ototoxicity scale in both ears at follow-up, and three (7%) of 45 patients developed grade 3-4 ototoxicity in one ear, although one later reverted to grade 2. The cumulative incidence of grade 3-4 hearing loss at 3 years was 12% (95% CI 4-25). At 5 years, it was 16% (95% CI 6-29). Pediatric Oncology Group hearing ototoxicity score at a follow-up of 5·0 years (IQR 2·9-6·4) was the same as at baseline or improved by 1 point in 34 (35%) of 98 ears, worsened by 1 point in 21 (21%), worsened by 2 points in 35 (36%), worsened by 3 points in six (6%), and worsened by 4 points in two (2%). Full Scale Intelligence Quotient decreased by 1·5 points (95% CI 0·9-2·1) per year after median follow-up up of 5·2 years (IQR 2·6-6·4), driven by decrements in processing speed and verbal comprehension index. Perceptual reasoning index and working memory did not change significantly. Cumulative incidence of any neuroendocrine deficit at 5 years was 55% (95% CI 41-67), with growth hormone deficit being most common. We recorded no cardiac, pulmonary, or gastrointestinal late toxic effects. 3-year progression-free survival was 83% (95% CI 71-90) for all patients. In post-hoc analyses, 5-year progression-free survival was 80% (95% CI 67-88) and 5-year overall survival was 83% (95% CI 70-90). INTERPRETATION: Proton radiotherapy resulted in acceptable toxicity and had similar survival outcomes to those noted with conventional radiotherapy, suggesting that the use of the treatment may be an alternative to photon-based treatments. FUNDING: US National Cancer Institute and Massachusetts General Hospital.

Down syndrome: Cognitive and behavioral functioning across the lifespan.

Individuals with Down syndrome (DS) commonly possess unique neurocognitive and neurobehavioral profiles that emerge within specific developmental periods. These profiles are distinct relative to others with similar intellectual disability (ID) and reflect underlying neuroanatomic findings, providing support for a distinctive phenotypic profile. This review updates what is known about the cognitive and behavioral phenotypes associated with DS across the lifespan. In early childhood, mild deviations from neurotypically developing trajectories emerge. By school-age, delays become pronounced. Nonverbal skills remain on trajectory for mental age, whereas verbal deficits emerge and persist. Nonverbal learning and memory are strengths relative to verbal skills. Expressive language is delayed relative to comprehension. Aspects of language skills continue to develop throughout adolescence, although language skills remain compromised in adulthood. Deficits in attention/executive functions are present in childhood and become more pronounced with age. Characteristic features associated with DS (cheerful, social nature) are personality assets. Children are at a lower risk for psychopathology compared to other children with ID; families report lower levels of stress and a more positive outlook. In youth, externalizing behaviors may be problematic, whereas a shift toward internalizing behaviors emerges with maturity. Changes in emotional/behavioral functioning in adulthood are typically associated with neurodegeneration and individuals with DS are higher risk for dementia of the Alzheimer's type. Individuals with DS possess many unique strengths and weaknesses that should be appreciated as they develop across the lifespan. Awareness of this profile by professionals and caregivers can promote early detection and support cognitive and behavioral development.

Long term neuropsychological outcomes of a pediatric ETANTR brain tumor: A case study.

Survivors of pediatric brain tumors are at high risk for long-term neuropsychological difficulties. In the current case study, we present longitudinal neuropsychological data spanning 10 years (from age 9 to 19 years) of a patient with a rare, very large, bifrontal, embryonal tumor with abundant neuropil and true rosettes (ETANTR), which is typically associated with poor survivorship and significant neurological impact. Results demonstrated that the patient had largely intact cognitive functioning with specific difficulties in executive functioning, fine motor skills, and adaptive functioning at her most recent neuropsychology 10-year follow-up. These results highlight outcomes for a patient with remarkable resiliency in the context of numerous risk factors (a very large tumor size, multi-modal treatment, and seizure history). Patient protective factors (a high level of cognitive reserve, family support, and appropriate comprehensive educational services) likely contributed to the patient's favorable neuropsychological outcome. The patient's age at brain tumor diagnosis (9 years) and associated treatment was at a critical period of development for emerging higher order cognitive functions which likely impacted acquisition of executive functioning skills and secondarily adaptive skill outcomes. Consequently, pediatric brain tumor survivors with ETANTR or other frontal tumors require targeted screening of executive functions and proactive interventions.

The neuroanatomical phenotype of tuberous sclerosis complex: focus on radial migration lines.

INTRODUCTION: The contribution of radial migration lines (RMLs) to the neuroanatomical and neurocognitive phenotype of tuberous sclerosis complex (TSC) is unclear. The aim of this study was to perform a comprehensive evaluation of the neuroradiological phenotype of TSC, distinguishing RMLs from normal-appearing white matter (NAWM) using diffusion tensor imaging (DTI) and volumetric fluid-attenuated inversion recovery imaging. METHODS: Magnetic resonance images of 30 patients with TSC were evaluated. The frequencies of RMLs, tubers, and subependymal nodules (SENs) were determined for every hemispheric lobe. Cerebellar lesions and subependymal giant cell tumors were counted. DTI metrics were obtained from the NAWM of every hemispheric lobe and from the largest RML and tuber. Analyses of variance and correlations were performed to investigate the associations between neuroanatomical characteristics and relationships between RML frequency and neurocognitive outcomes. NAWM DTI metrics were compared with measurements of 16 control patients. RESULTS: A mean of 47 RMLs, 27 tubers, and 10 SENs were found per patient, and the frequencies of these lesions were strongly correlated (p < 0.001). RML fractional anisotropy and mean diffusivity were strongly inversely correlated (p = 0.003). NAWM DTI metrics were similar to the controls (p = 0.26). RML frequency was strongly associated with age of seizure onset (p = 0.003), intelligence outcomes (p = 0.01), and level of autistic features (p = 0.007). CONCLUSION: A detailed neuroradiological phenotype is presented, showing that RMLs are the most frequent neuroanatomical lesion, are responsible for white matter DTI abnormalities, and are strongly associated with age of seizure onset, intelligence outcomes, and level of autistic features.

Understanding relationships between autism, intelligence, and epilepsy: a cross-disorder approach.

AIM: As relationships between autistic traits, epilepsy, and cognitive functioning remain poorly understood, these associations were explored in the biologically related disorders tuberous sclerosis complex (TSC), neurofibromatosis type 1 (NF1), and epilepsy. METHOD: The Social Responsiveness Scale (SRS), a quantitative measure of autistic traits, was distributed to caregivers or companions of patients with TSC, NF1, and childhood-onset epilepsy of unknown cause (EUC), and these results were compared with SRS data from individuals with idiopathic autism spectrum disorders (ASDs) and their unaffected siblings. Scores and trait profiles of autistic features were compared with cognitive outcomes, epilepsy variables, and genotype. RESULTS: A total of 180 SRS questionnaires were completed in the TSC, NF1, and EUC outpatient clinics at the Massachusetts General Hospital (90 females, 90 males; mean age 21 y, range 4-63 y), and SRS data from 210 patients with ASD recruited from an autism research collaboration (167 males, 43 females; mean age 9 y, range 4-22 y) and 130 unaffected siblings were available. Regression models showed a significant association between SRS scores and intelligence outcomes (p<0.001) and various seizure variables (p<0.02), but not with a specific underlying disorder or genotype. The level of autistic features was strongly associated with intelligence outcomes in patients with TSC and epilepsy (p<0.01); in patients with NF1 these relationships were weaker (p=0.25). For all study groups, autistic trait subdomains covaried with neurocognitive comorbidity, with endophenotypes similar to that of idiopathic autism. INTERPRETATION: Our data show that in TSC and childhood-onset epilepsy, the severity and phenotype of autistic features are inextricably linked with intelligence and epilepsy outcomes. Such relationships were weaker for individuals with NF1. Findings suggest that ASDs are not specific in these conditions.

Cognitive and adaptive development of patients with tuberous sclerosis complex: a retrospective, longitudinal investigation.

OBJECTIVE: The aim of the work described here was to systematically analyze the developmental trajectory of patients with tuberous sclerosis complex (TSC). METHODS: A retrospective longitudinal chart review was performed, selecting patients who received multiple neuropsychological assessments. Intellectual/Developmental Quotients, Adaptive Behavior Composite scores, and clinical data were collected. On available EEGs, interictal epileptiform discharges were counted. RESULTS: Sixty-six (18%) patients with TSC received multiple cognitive and adaptive development assessments. The mean intelligence of this study group remained relatively stable, albeit variable. Significant decline in adaptive functioning was observed, associated with lower age at seizure onset. Patients who underwent neurosurgery prior to baseline testing showed cognitive improvement. Developmental declines were significantly associated with increased numbers of antiepileptic drugs, with a trend toward association with mutation type and interictal epileptiform discharges. CONCLUSION: This study suggests that the developmental course of patients with TSC may be altered by epilepsy comorbidity and neurosurgery, underlining the need for early and effective interventions in this population.

Correction: Hom et al. Cognitive Function during the Prodromal Stage of Alzheimer's Disease in Down Syndrome: Comparing Models. BrainSci. 2021, 11, 1220.

We would like to submit the following correction to our recently published paper [...].

A modified Cued Recall Test for detecting prodromal AD in adults with Down syndrome.

Introduction: The development of valid methods to diagnose prodromal Alzheimer's disease (AD) in adults with Down syndrome (DS) is one of the many goals of the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS). Methods: The diagnostic utility of a modified Cued Recall Test (mCRT) was evaluated in 332 adults with DS ranging from 25 to 81 years of age. Total recall was selected a priori, as the primary indicator of performance. Multiple regression and receiver-operating characteristic (ROC) analyses were used to compare diagnostic groups. Results: Performance on the mCRT, as indicated by the total recall score, was highly sensitive to differences between diagnostic groups. ROC areas under the curve (AUCs) ranging from 0.843 to 0.955, were observed. Discussion: The mCRT has strong empirical support for its use in clinical settings, as a valuable tool in studies targeting biomarkers of AD, and as a potential outcome measure in clinical trials targeting AD in this high-risk population.

Evaluation of Upper Airway Stimulation for Adolescents With Down Syndrome and Obstructive Sleep Apnea.

Importance: Patients with Down syndrome have a high incidence of persistent obstructive sleep apnea (OSA) and limited treatment options. Upper airway hypoglossal stimulation has been shown to be effective for adults with OSA but has not yet been evaluated for pediatric populations. Objective: To evaluate the safety and effectiveness of upper airway stimulation for adolescent patients with Down syndrome and severe OSA. Design, Setting, and Participants: This prospective single-group multicenter cohort study with 1-year follow-up was conducted between April 1, 2015, and July 31, 2021, among a referred sample of 42 consecutive adolescent patients with Down syndrome and persistent severe OSA after adenotonsillectomy. Intervention: Upper airway stimulation. Main Outcomes and Measures: The prespecified primary outcomes were safety and the change in apnea-hypopnea index (AHI) from baseline to 12 months postoperatively. Polysomnographic and quality of life outcomes were assessed at 1, 2, 6, and 12 months postoperatively. Results: Among the 42 patients (28 male patients [66.7%]; mean [SD] age, 15.1 [3.0] years), there was a mean (SD) decrease in AHI of 12.9 (13.2) events/h (95% CI, -17.0 to -8.7 events/h). With the use of a therapy response definition of a 50% decrease in AHI, the 12-month response rate was 65.9% (27 of 41), and 73.2% of patients (30 of 41) had a 12-month AHI of less than 10 events/h. The most common complication was temporary tongue or oral discomfort, which occurred in 5 patients (11.9%). The reoperation rate was 4.8% (n = 2). The mean (SD) improvement in the OSA-18 total score was 34.8 (20.3) (95% CI, -42.1 to -27.5), and the mean (SD) improvement in the Epworth Sleepiness Scale score was 5.1 (6.9) (95% CI, -7.4 to -2.8). The mean (SD) duration of nightly therapy was 9.0 (1.8) hours, with 40 patients (95.2%) using the device at least 4 hours a night. Conclusions and Relevance: Upper airway stimulation was able to be safely performed for 42 adolescents who had Down syndrome and persistent severe OSA after adenotonsillectomy with positive airway pressure intolerance. There was an acceptable adverse event profile with high rates of therapy response and quality of life improvement. Trial Registration: ClinicalTrials.gov Identifier: NCT02344108.

Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine in Adults With Down Syndrome: A Phase 1b Randomized Clinical Trial.

Importance: Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-ß (Aß). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aß pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined. Objective: To assess the safety and tolerability of the ACI-24 vaccine among adults with DS as well as its ability to induce immunogenicity measured by anti-Aß immunoglobulin G titers. Design, Setting, and Participants: This multicenter double-blind placebo-controlled dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020. A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate. Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27, 2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts (8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an additional 48 weeks of safety follow-up. Interventions: Participants were randomized to receive 7 subcutaneous injections of ACI-24, 300 µg or 1000 µg, or placebo. Main Outcomes and Measures: Primary outcomes were measures of safety and tolerability as well as antibody titers. Results: Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years; 9 participants were women, and 7 were men. All participants were White, and 1 participant had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events [83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events [85.6%]). No amyloid-related imaging abnormalities with edema or cerebral microhemorrhage and no evidence of central nervous system inflammation were observed on magnetic resonance imaging scans. Increases in anti-Aß immunoglobulin G titers were observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 µg and 2 receiving 1000 µg) compared with 0 participants receiving placebo. In addition, a greater increase was observed in plasma Aß1-40 and Aß1-42 levels among individuals receiving ACI-24. Conclusions and Relevance: In this study, the ACI-24 vaccine was safe and well tolerated in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target engagement were observed, and anti-Aß antibody titers were not associated with any adverse findings. These results support progression to clinical trials using an optimized formulation of the ACI-24 vaccine among individuals with DS. Trial Registration: ClinicalTrials.gov Identifier: NCT02738450.