Growth Hormone Treatment in Patients With KBG Syndrome: Novel Insights, Challenges and Recommendations From Six New Patients and Literature Review.

KBG syndrome is one of the most frequent neurodevelopmental disorders and is caused by ANKRD11 variants. Postnatal short stature is observed in ~50% of patients. Recombinant human growth hormone (rhGH) has become a valuable treatment for patients with growth hormone deficiency (GHD) along with Prader-Willi and Turner syndrome.

Genome-wide association analyses identify candidate loci for amyloid imaging and plasma biomarkers in adults with Down syndrome.

Background: People with Down syndrome (DS) overproduce amyloid-beta (Aβ) due to triplication of the amyloid precursor protein (APP) gene on chromosome 21, and consequently accumulate brain amyloid load at younger ages. We conducted genome-wide association (GWA) analyses on amyloid imaging and plasma biomarkers to discern the genetic architecture of amyloid burden in DS.

Methods: GWA analyses were performed on amyloid positron emission tomography (PET) and plasma biomarkers (Aβ40, Aβ42, Aβ42/40 ratio) in participants from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) and on plasma Aβ biomarkers available in an independent DS cohort, followed by meta-analysis of plasma Aβ biomarker data.

Joint spatial associations of amyloid beta and tau pathology in Down syndrome and preclinical Alzheimer's disease: Cross-sectional associations with early cognitive impairments.

Introduction: Individuals with Down syndrome (DS) have elevated risks for Alzheimer's disease (AD) due to amyloid beta (Aβ) precursor protein overexpression, with nearly all developing AD pathology by age 40 at autopsy. This study examined spatial associations between Aβ and tau burden in DS and neurotypical aging.

Methods: Data included 145 DS (25-67 years) and 191 neurotypical aging individuals (63-89 years).

Hyaluronan: An Architect and Integrator for Cancer and Neural Diseases.

Hyaluronan (HA) is essentially secreted by every cell and plays a critical role in maintaining normal cell physiology. While the structure and function of HA have been extensively investigated, questions regarding the sizes and conformation of HA under physiological and inflamed conditions, in relevance to its functions, remain elusive. In this article, we update our knowledge of the HA functional properties, including binding proteins and their signaling networks, as well as matrix formation, which can potentially induce phase separation and affect the mobility and behavior of small molecules, proteins, and cells.

Brain glymphatic fluid mapping in Alzheimer's disease: a human MRI and PET study.

Glymphatic system has been identified as a fluid exchange network in brain parenchymal for removal of toxic metabolites in Alzheimer's disease. However, a clinically feasible, accurate, and non-invasive imaging technique for mapping global glymphatic fluid distribution throughout the entire brain and monitoring its dysfunction in Alzheimer's disease is currently lacking. This cross-sectional retrospective study aims to compare three MRI-based measures of the glymphatic system structural alterations, a novel multi-echo T2 relaxometry-based parenchymal CSF (pCSF) mapping, T2 weighted-based segmented perivascular space burden, and diffusion tensor imaging-based free-water mapping.

Depression Symptom Trajectories in Mothers With the FMR1 Premutation Vary by CGG Repeat Length: A Longitudinal Study of 73 Women Spanning 20-75 Years of Age.

Women with the FMR1 premutation (FXpm) are at heightened genetic vulnerability for depression, with risk compounded by the stressors of parenting a disabled child. Although risk factors persist as FXpm women age, depression in FXpm mothers during midlife and old age is poorly characterized. This study used an accelerated longitudinal design to capture the trajectory of depressive symptoms in 73 FXpm mothers across 20-75 years of age.

Call category classification of the isolation-induced ultrasonic vocalizations emitted by BTBR TItpr3/J mouse pups exposed to different perinatal diets.

Autism spectrum disorder (ASD) is characterized by deficits in social communication and repetitive behaviors/restricted interests that may be diagnosed as early as 2 years of age. This suggests that the pathology underlying the disorder is present during early development, including gestation. This early developmental period is affected by maternal nutrition.

Alzheimer's disease patient brain extracts induce multiple pathologies in novel vascularized neuroimmune organoids for disease modeling and drug discovery.

Alzheimer's Disease (AD) is the most common cause of dementia, afflicting 55 million individuals worldwide, with limited treatment available. Current AD models mainly focus on familial AD (fAD), which is due to genetic mutations. However, models for studying sporadic AD (sAD), which represents over 95% of AD cases without specific genetic mutations, are severely limited.

The Cardiovascular Manifestations and Management Recommendations for Ogden Syndrome.

The NatA complex is composed of the NAA10, NAA15, and HYPK sub-units. It is primarily responsible for N-terminal acetylation, a critical post-translational modification in eukaryotes. Pathogenic variants within NAA10 cause Ogden Syndrome (OS), which is characterized by varying degrees of intellectual disability, hypotonia, developmental delay, and cardiac abnormalities.

Modified Cued Recall Test: Longitudinal Analysis of Test Versions and Item Recall in Adults With Down Syndrome.

Background: Adults with Down syndrome (DS) have an elevated risk and early age of onset for Alzheimer's disease (AD). To support upcoming clinical AD trials, there is a critical need to establish cognitive outcome measures that can be used to capture intervention effects. One measure that has successfully been used to detect AD-related cognitive decline in the DS population is a measure of episodic memory, the modified Cued Recall Test (mCRT).

Behavioral and psychological symptoms of dementia and Alzheimer's disease progression in Down syndrome.

Background: Adults with Down syndrome (DS) have a 90% lifetime risk for Alzheimer's disease (AD), with neurobiological pathology present decades prior to dementia onset. The profile and timing of cognitive decline in DS is well-documented. However, there is a small body of research on whether Behavioral and Psychological Symptoms of Dementia (BPSD) occur early on in the progression of AD in DS and are associated with early AD pathology (i.

Neuroanatomical features of NAA10 and NAA15-related neurodevelopmental syndromes.

Background: NAA10-related and NAA15-related neurodevelopmental (ND) syndromes present with intellectual disability, hypotonia, cardiac abnormalities, and delayed development. While data exists on the clinical manifestations of these conditions, there are few reports describing the neuroanatomical abnormalities present on imaging.

Objective: We aim to provide neuroimaging analyses for a subset of probands with NAA10- and NAA15-related neurodevelopmental symptoms and assess the severity and number of neuroanatomical anomalies and their associated functional impairments to better understand the pathophysiology of these disease processes.

Rhythmic TDP-43 affects RNA splicing of USP13, resulting in alteration of BMAL1 ubiquitination.

Circadian rhythm disorders are common characteristics of neurodegenerative diseases. The pathological aggregation of transactive response DNA-binding protein 43 (TDP-43) is associated with multiple neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, the relationship between TDP-43 and circadian rhythm remains unknown.

P253 Next-generation phenotyping facilitates the identification of structural brain malformations in rare disorders through computational brain MRI analysis.

Introduction: Many rare disorders, particularly neurodevelopmental conditions, manifest structural brain malformations. Just as dysmorphologists rely on facial gestalt recognition to identify syndromes, radiologists and neurologists face similar challenges in identifying the "brain gestalt" of rare disorders-especially when encountering rare conditions or those they have not previously seen. Next-generation phenotyping (NGP) has been proven capable of supporting clinicians in recognizing facial dysmorphic patterns associated with the underlying syndrome through training on thousands of patient photographs.

Reduced Respiratory Sinus Arrhythmia in Infants with the Premutation.

The fragile X premutation (FXpm) is caused by a CGG repeat expansion on the gene. In adults, FXpm is linked with autonomic nervous system (ANS) dysfunction and impairment is associated with CGG repeat length. Given scant infancy research, we examined ANS functioning, via respiratory sinus arrhythmia (RSA) and interbeat interval (IBI), in 82 FXpm and neurotypical infants and their associations with CGG repeats.

Natural History of NAA15 -Related Neurodevelopmental Disorder Through Adolescence.

The NatA N-terminal acetyltransferase complex is composed of the NAA10 catalytic subunit and the auxiliary subunits NAA15 and HYPK. While those with variants in the enzymatic subunit develop Ogden Syndrome, individuals with variants in the NAA15 coding region develop NAA15-related neurodevelopmental syndrome, which presents with a wide array of manifestations that affect the heart, brain, musculoskeletal system, and behavioral and cognitive development. We tracked a cohort of 27 participants (9 females and 18 males) with pathogenic NAA15 variants over time and administered the Vineland-3 assessment to assess their adaptive functioning.

Validity of one-time assessments for identifying prodromal Alzheimer's disease in adults with Down syndrome.

Introduction: New Alzheimer's disease (AD) treatments have created an urgent need for accurate early diagnosis of high-risk adults with Down syndrome (DS), distinguishing prodromal DS-AD symptoms from lifelong cognitive impairments. Often, clinicians will need to evaluate dementia status during a single assessment, and here we describe empirically supported methods effective under such circumstances.

Methods: Archived data collected between 1987 and 2017 included longitudinal findings for 144 individuals maintaining cognitive stability and 126 developing prodromal DS-AD.

Eye Tracking as a Tool for Detecting Alzheimer's Disease in People With Down Syndrome.

Background: Adults with Down syndrome (DS) experience an increased risk of Alzheimer's disease (AD). Valid cognitive assessments for adults with DS with severe/profound intellectual disability (ID) are needed. It is unclear whether eye tracking is feasible for detecting AD in DS.

Age-related p53 SUMOylation accelerates senescence and tau pathology in Alzheimer's disease.

Aging is a major risk factor for Alzheimer's disease (AD). With the prevalence of AD increased, a mechanistic linkage between aging and the pathogenesis of AD needs to be further addressed. Here, we report that a small ubiquitin-related modifier (SUMO) modification of p53 is implicated in the process which remarkably increased in AD patient's brain.

DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive.

Novel Copy Number Deletion Involving Associated With Epilepsy, Tremor, and Intellectual Disability.

Copy number variations (CNVs) contribute to various disorders including intellectual disability, developmental disorders, and cancer. This study identifies a de novo 2.62 Mb deletion at 6q22.

Single-nucleus RNA sequencing reveals distinct pathophysiological trophoblast signatures in spontaneous preterm birth subtypes.

Spontaneous preterm birth (sPTB) poses significant challenges, affecting neonatal health and neurodevelopmental outcomes worldwide. The specific effects of placental trophoblasts on the pathological development of sPTB subtypes-preterm premature rupture of fetal membranes (pPROM) and spontaneous preterm labor (sPTL)-are not fully understood, making it crucial to uncover these impacts for the development of effective therapeutic strategies. Using single-nucleus RNA sequencing, we investigated transcriptomic and cellular differences at the maternal-fetal interface in pPROM and sPTL placentas.

Quantitative and longitudinal assessment of human placental inflammation using diffusion basis spectrum imaging.

Besides exchanging nutrients, gases, and wastes, placenta is an intermediary between maternal and fetal immune systems. However, no method exists to safely image and monitor placental inflammation during pregnancy. We customized a Magnetic Resonance Imaging (MRI) method, diffusion basis spectrum imaging (DBSI), to measure immune cells in placenta.

Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder.

Background: Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice.