Assessing amyloid PET positivity and cognitive function in Down syndrome to guide clinical trials targeting amyloid.

INTRODUCTION: Trisomy 21, or Down syndrome (DS), predisposes individuals to early-onset Alzheimer's disease (AD). While monoclonal antibodies (mAbs) targeting amyloid are approved for older AD patients, their efficacy in DS remains unexplored. This study examines amyloid positron emission tomography (PET) positivity (A+), memory function, and clinical status across ages in DS to guide mAb trial designs. METHODS: Cross-sectional data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS) was analyzed. PET amyloid beta in Centiloids classified amyloid status using various cutoffs. Episodic memory was assessed using the modified Cued Recall Test, and clinical status was determined through consensus processes. RESULTS: Four hundred nine DS adults (mean age = 44.83 years) were evaluated. A+ rates increased with age, with mean amyloid load rising significantly. Memory decline and cognitive impairment are also correlated with age. DISCUSSION: These findings emphasize the necessity of tailoring mAb trials for DS, considering age-related AD characteristics. HIGHLIGHTS: There is rapid increase in prevalence of amyloid beta (Aß) positron emission tomography (PET) positivity in Down syndrome (DS) after the age of 40 years. Aß PET positivity thresholds have significant impact on prevalence rates in DS. There is a significant lag between Aß PET positivity and clinical symptom onset in DS.

AT(N) biomarker profiles and Alzheimer's disease symptomology in Down syndrome.

INTRODUCTION: Down syndrome (DS) is a genetic cause of early-onset Alzheimer's disease (AD). The National Institute on Aging-Alzheimer's Association AT(N) Research Framework is a staging model for AD biomarkers but has not been assessed in DS. METHOD: Data are from the Alzheimer's Biomarker Consortium-Down Syndrome. Positron emission tomography (PET) amyloid beta (Aß; 15 mCi of [11 C]Pittsburgh compound B) and tau (10 mCi of [18 F]AV-1451) were used to classify amyloid (A) -/+ and tau (T) +/-. Hippocampal volume classified neurodegeneration (N) -/+. The modified Cued Recall Test assessed episodic memory. RESULTS: Analyses included 162 adults with DS (aged M = 38.84 years, standard deviation = 8.41). Overall, 69.8% of participants were classified as A-/T-/(N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. Participants deemed cognitively stable were most likely to be A-T-(N)- and A+T-(N)-. Tau PET (T+) most closely aligning with memory impairment and AD clinical status. DISCUSSION: Findings add to understanding of AT(N) biomarker profiles in DS. HIGHLIGHTS: Overall, 69.8% of adults with Down syndrome (DS) aged 25 to 61 years were classified as amyloid (A)-/tau (T)-/neurodegeneration (N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. The AT(N) profiles were associated with clinical Alzheimer's disease (AD) status and with memory performance, with the presence of T+ aligned with AD clinical symptomology. Findings inform models for predicting the transition to the prodromal stage of AD in DS.

Characterizing the emergence of amyloid and tau burden in Down syndrome.

INTRODUCTION: Almost all individuals with Down syndrome (DS) will develop neuropathological features of Alzheimer's disease (AD). Understanding AD biomarker trajectories is necessary for DS-specific clinical interventions and interpretation of drug-related changes in the disease trajectory. METHODS: A total of 177 adults with DS from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) underwent positron emission tomography (PET) and MR imaging. Amyloid-beta (Aß) trajectories were modeled to provide individual-level estimates of Aß-positive (A+) chronicity, which were compared against longitudinal tau change. RESULTS: Elevated tau was observed in all NFT regions following A+ and longitudinal tau increased with respect to A+ chronicity. Tau increases in NFT regions I-III was observed 0-2.5 years following A+. Nearly all A+ individuals had tau increases in the medial temporal lobe. DISCUSSION: These findings highlight the rapid accumulation of amyloid and early onset of tau relative to amyloid in DS and provide a strategy for temporally characterizing AD neuropathology progression that is specific to the DS population and independent of chronological age. HIGHLIGHTS: Longitudinal amyloid trajectories reveal rapid Aß accumulation in Down syndrome NFT stage tau was strongly associated with A+ chronicity Early longitudinal tau increases were observed 2.5-5 years after reaching A.

Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome.

INTRODUCTION: This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. METHODS: AD polygenic risk scores (PRS) were tested for association with DS-related traits. RESULTS: The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRSAPOE , p = 2.84 × 10-4 ; PRS excluding APOE, PRSnonAPOE , p = 1.60 × 10-2 ). PRSAPOE exhibited significant associations with Aß42, tTau, pTau, and Aß42/40 ratio in DS. DISCUSSION: These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits. HIGHLIGHTS: Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults.

Parent couple conflict and emotional and behavioral problems in youth with autism: Longitudinal investigation of bidirectional effects.

Families of youth with autism spectrum disorder (ASD) are vulnerable to maladaptive psychosocial experiences, including elevated youth emotional and behavioral problems (EBPs) and poor parent couple relationship outcomes. Yet, the extent to which these family psychosocial experiences are intertwined has been given little research attention. The present study longitudinally investigated the bidirectional associations between parent couple conflict (PCC) and youth EBPs in 188 families of children and adolescents with ASD (initially aged 5 to 12 years) across four time points (T1, T2, T3, T4), each spaced 12 months apart. Mother- and father-report of youth EBPs and PCC were entered into a cross-lagged panel model. After adjusting for youth age and intellectual disability status and parent education and couple relationship length, the results indicated that father-report of PCC predicted increased youth EBPs 12 months later (T1→T2 and T2→T3). In addition, father-report of youth EBPs predicted increased PCC 12 months later (T3→T4). Mother-report did not demonstrate cross-lagged effects. The findings suggest that fathers' perceptions of PCC and youth emotional and behavioral functioning are transactionally related, highlighting the need for family-wide interventions.

Does Employment Complexity Promote Healthy Cognitive Aging in Down Syndrome?

Adults with Down syndrome (DS) experience high risk for Alzheimer's disease (AD), but there is variability in the timing of transition from a cognitively stable state to prodromal AD and dementia. The present study examined the association between a modifiable lifestyle factor, employment complexity, and cognitive decline across two time points in adults with DS. Employment complexity, defined as the degree of problem-solving or critical thinking required for employment activities, was operationalized using the Dictionary of Occupational Titles, a system which classifies occupations based on three categories: Data, People, and Things. Eighty-seven adults with DS (M = 36.28 years, SD = 6.90 years) were included in analyses. Partial correlations revealed that lower employment complexity involving People and Things were associated with increased dementia symptoms. Lower employment complexity involving Things was also associated with memory decline. These findings have implications for vocational programs focused on job training and placement for adults with DS.

Marital satisfaction, parenting styles, and child outcomes in families of autistic children.

Theory and research on the general population suggest that parents' marital relationship quality is associated with children's emotional and behavioral functioning directly, as well as indirectly, by affecting parenting attitudes and behaviors. However, little has been done to investigate the potential connection among parent marital satisfaction, parenting styles, and outcomes for autistic children. Using longitudinal data collected from 188 couples parenting an autistic child, this study tested the time-ordered indirect effect of parent marital satisfaction (assessed at Time 1) on the internalizing and externalizing symptoms (assessed at Time 3) of autistic children (originally aged 5-12 years) via parenting styles (assessed at Time 2) using actor-partner interdependence modeling extended to mediation. Results indicated that a lower level of marital satisfaction at Time 1 predicted impaired child outcomes at Time 3 via its impact on parenting style at Time 2. For both parents, lower marital satisfaction predicted more child externalizing symptoms via reports of more authoritarian parenting style. Lower marital satisfaction in mothers at Time 1 was also associated with higher levels of child internalizing symptoms at Time 3 via increased authoritarian parenting in mothers. No partner effects were found. A family-wide approach that includes support for the parent marital relationship, which may have downstream effects on parenting, is important for promoting optimal emotional and behavioral health in autistic children.

La teoría y las investigaciones sobre la población en general indican que la calidad de la relación conyugal de los padres está asociada con el funcionamiento conductual y emocional de los niños tanto directamente como indirectamente, ya que afecta las actitudes y las conductas de crianza. Sin embargo, se ha hecho poco para investigar la posible conexión entre la satisfacción conyugal de los padres, los estilos de crianza y las consecuencias en los niños autistas. Utilizando datos longitudinales recogidos de 188 parejas que criaban a un niño autista, este estudio evaluó el efecto indirecto según el orden del tiempo de la satisfacción conyugal de los padres (evaluada en el primer intervalo) en las síntomas de exteriorización y de interiorización (evaluados en el tercer intervalo) de los niños autistas (inicialmente de entre 5 y 12 años) mediante los estilos de crianza (evaluados en el segundo intervalo) utilizando un modelo de interdependencia actor-pareja extendido a la mediación. Los resultados indicaron que un nivel más bajo de satisfacción conyugal en el primer intervalo predijo consecuencias disfuncionales en los niños en el tercer intervalo mediante su efecto en el estilo de crianza en el segundo intervalo. Para ambos padres, una menor satisfacción conyugal predijo más síntomas de exteriorización de los niños mediante informes de un estilo de crianza más autoritario. Una menor satisfacción conyugal en las madres en el primer intervalo también estuvo asociada con niveles más altos de síntomas de interiorización en los niños en el tercer intervalo mediante una mayor crianza autoritaria en las madres. No se encontraron efectos de la pareja. Con el fin de promover una salud conductual y emocional óptima en los niños autistas, es importante implementar un método para toda la familia que incluya apoyo para la relación conyugal de los padres, la cual puede tener efectos posteriores en la crianza.

PET measurement of longitudinal amyloid load identifies the earliest stages of amyloid-beta accumulation during Alzheimer's disease progression in Down syndrome.

INTRODUCTION: Adults with Down syndrome (DS) are predisposed to Alzheimer's disease (AD) and reveal early amyloid beta (Aß) pathology in the brain. Positron emission tomography (PET) provides an in vivo measure of Aß throughout the AD continuum. Due to the high prevalence of AD in DS, there is need for longitudinal imaging studies of Aß to better characterize the natural history of Aß accumulation, which will aid in the staging of this population for clinical trials aimed at AD treatment and prevention. METHODS: Adults with DS (N = 79; Mean age (SD) = 42.7 (7.28) years) underwent longitudinal [C-11]Pittsburgh compound B (PiB) PET. Global Aß burden was quantified using the amyloid load metric (AßL). Modeled PiB images were generated from the longitudinal AßL data to visualize which regions are most susceptible to Aß accumulation in DS. AßL change was evaluated across Aß(-), Aß-converter, and Aß(+) groups to assess longitudinal Aß trajectories during different stages of AD-pathology progression. AßL change values were used to identify Aß-accumulators within the Aß(-) group prior to reaching the Aß(+) threshold (previously reported as 20 AßL) which would have resulted in an Aß-converter classification. With knowledge of trajectories of Aß(-) accumulators, a new cutoff of Aß(+) was derived to better identify subthreshold Aß accumulation in DS. Estimated sample sizes necessary to detect a 25% reduction in annual Aß change with 80% power (alpha 0.01) were determined for different groups of Aß-status. RESULTS: Modeled PiB images revealed the striatum, parietal cortex and precuneus as the regions with earliest detected Aß accumulation in DS. The Aß(-) group had a mean AßL change of 0.38 (0.58) AßL/year, while the Aß-converter and Aß(+) groups had change of 2.26 (0.66) and 3.16 (1.34) AßL/year, respectively. Within the Aß(-) group, Aß-accumulators showed no significant difference in AßL change values when compared to Aß-converter and Aß(+) groups. An Aß(+) cutoff for subthreshold Aß accumulation was derived as 13.3 AßL. The estimated sample size necessary to detect a 25% reduction in Aß was 79 for Aß(-) accumulators and 59 for the Aß-converter/Aß(+) group in DS. CONCLUSION: Longitudinal AßL changes were capable of distinguishing Aß accumulators from non-accumulators in DS. Longitudinal imaging allowed for identification of subthreshold Aß accumulation in DS during the earliest stages of AD-pathology progression. Detection of active Aß deposition evidenced by subthreshold accumulation with longitudinal imaging can identify DS individuals at risk for AD development at an earlier stage.

Trajectories of Dysregulation in Children with Autism Spectrum Disorder.

Objective: This study determined whether child and family environment factors are associated with differences in developmental trajectories of emotional and behavioral dysregulation in children with autism spectrum disorder (ASD).Method: Participants included 186 families of a child with ASD (5-12 years old at baseline; 86% male; 83% non-Hispanic Caucasian; 35% comorbid intellectual disability). At each of the four time points (each spaced 12 months apart), mothers and fathers within each family completed well-validated measures on their own mental health, their child's dysregulation, their parent-child relationship, and their parent couple relationship. Longitudinal multi-level modeling was used to describe trajectories of dysregulation across 3 years and test whether parent depression, closeness in the parent-child relationship, and positive parent dyadic coping were associated with differences in child trajectories.Results: On average, child dysregulation decreased across time. Closer mother-child and father-child relationship quality was associated with lower baseline dysregulation. More severe child restricted and repetitive behaviors, fewer maternal depression symptoms, and more positive parent dyadic coping were associated with declines in child dysregulation over time.Conclusions: On average, children with ASD become less dysregulated across time. However, there is important variability in dysregulation trajectories of children with ASD. Children with ASD who have a high (versus low) severity of restricted and repetitive behaviors appear to be at risk for greater dysregulation. The family environment, and specifically a closer parent-child relationship, better maternal mental health, and more positive couple coping, may contribute to a pattern of improved child regulation across time in ASD.

Use and Benefit of Dyadic Coping for Couple Relationship Satisfaction in Parents of Children with Autism.

Parents of children with autism spectrum disorder (ASD) are at increased risk for unsatisfying and conflict-ridden couple relationships (i.e., marital or romantic partner relationships). There is a critical need to identify the couple-level processes that contribute to this risk. The current study examined the use of dyadic coping, defined as the appraisals and behaviors that partners in relationships use and receive to manage stressors, and to examine whether dyadic coping mediated the association between parenting stress and couple relationship satisfaction in parents who have a child with ASD and in parents who do not have a child with ASD. In total, 184 couples that had a child with ASD (aged 5-12 years) and comparison group of 183 couples who have a child without a neurodevelopmental condition participated in the study. A multivariate analysis of covariance indicated that parents of children with ASD reported less positive and more negative dyadic coping than did parents in the comparison group. Hierarchical linear modeling indicated that dyadic coping mediated the association between parenting stress and couple relationship satisfaction. Findings have important implications for programs aimed at enhancing parent couple relationship in families of children with ASD.

Los padres de niños con trastorno del espectro autista (TEA) corren mayor riesgo de tener relaciones de pareja insatisfactorias y conflictivas (p. ej.: relaciones de pareja o conyugales). Existe una necesidad imperiosa de reconocer los procesos a nivel de la pareja que contribuyen a este riesgo. El presente estudio analizó el uso del afrontamiento diádico, definido como las evaluaciones y las conductas que los integrantes de la pareja usan y reciben para manejar los factores desencadenantes de estrés, y si este afrontamiento sirvió como mediador de la asociación entre el estrés por la crianza y la satisfacción con la relación de pareja en los padres que tienen un niño con TEA y en los padres que no tienen un niño con TEA. Participaron en el estudio un total de 184 parejas que tenían un hijo con TEA (de entre 5 y 12 años) y un grupo comparativo de 183 parejas que tenían un hijo sin un trastorno del desarrollo neurológico. Un análisis multifactorial de la covarianza indicó que los padres de los niños con TEA informaron un afrontamiento diádico menos positivo y más negativo que los padres en el grupo de comparación. Los modelos lineales jerárquicos indicaron que el afrontamiento diádico sirvió como mediador de la asociación entre el estrés por la crianza y la satisfacción con la relación de pareja. Los resultados tienen consecuencias importantes para los programas orientados a mejorar la relación de los padres como pareja en las familias de niños con TEA.

Further understanding the connection between Alzheimer's disease and Down syndrome.

Improved medical care of individuals with Down syndrome (DS) has led to an increase in life expectancy to over the age of 60 years. In conjunction, there has been an increase in age-related co-occurring conditions including Alzheimer's disease (AD). Understanding the factors that underlie symptom and age of clinical presentation of dementia in people with DS may provide insights into the mechanisms of sporadic and DS-associated AD (DS-AD). In March 2019, the Alzheimer's Association, Global Down Syndrome Foundation and the LuMind IDSC Foundation partnered to convene a workshop to explore the state of the research on the intersection of AD and DS research; to identify research gaps and unmet needs; and to consider how best to advance the field. This article provides a summary of discussions, including noting areas of emerging science and discovery, considerations for future studies, and identifying open gaps in our understanding for future focus.

Psychological Well-Being and Parent-Child Relationship Quality in Relation to Child Autism: An Actor-Partner Modeling Approach.

Parents of children with autism spectrum disorder (ASD) often report poor psychological well-being, including a high level of parenting stress and depressive symptoms. Little is known about the extent to which poor parent psychological well-being alters the emotional quality of the parent-child relationship in a context of child ASD. This study examined the association between actor (one's own) and partner (one's partner's) level of parenting stress and depressive symptoms and the emotional quality of the parent-child relationship using a Five Minute Speech Sample (FMSS) in 150 families of children with ASD, aged 5-12 years (85.7% male). Mothers and fathers were aged 38.69 (SD = 5.62) and 40.76 (SD = 6.19), respectively; 76% of mothers and 68% of fathers had a college degree. Structural equation modeling, using Analysis of Moment Structures software, was used to test Actor-Partner Interdependence Models. Results indicated that mother's level of parenting stress and depressive symptoms were associated with her own FMSS Warmth and Criticism toward the child with ASD 12 months later in negative and positive directions. Mother's level of parenting stress was also negatively associated with father's FMSS Warmth toward the child with ASD 12 months later. Finally, father's level of parenting stress was positively associated with his FMSS Criticism toward the child with ASD. Overall, findings indicate that the mother-child and father-child relationship are both impacted by parent psychological well-being in families of children with ASD; however, actor effects are stronger for mothers and partner effects were only found for fathers. Implications for interventions are discussed.

Los padres de los niños con trastorno del espectro autista (TEA) generalmente informan un bienestar psicológico deficiente, como un alto nivel de estrés por la crianza y síntomas depresivos. Se sabe muy poco acerca de la medida en la que el bienestar psicológico deficiente de los padres altera la calidad emocional de la relación entre padres e hijos en un contexto de TEA de los niños. El presente estudio analizó la asociación entre el nivel de estrés por la crianza y los síntomas depresivos del actor (los de uno) y de la pareja (la pareja de uno) y la calidad emocional de la relación entre padres e hijos usando una muestra del habla de cinco minutos (Five Minute Speech Sample, FMSS) en 150 familias de niños con TEA, de entre 5 y 12 años (85.7% masculino). Las madres y los padres tenían 38.69 (Desviación Típica = 5.62) y 40.76 (Desviación Típica = 6.19) de edad, respectivamente; el 76 % de las madres y el 68 % de los padres tenía un título universitario. Para evaluar los modelos de interdependencia actor-pareja se utilizaron los modelos de ecuaciones estructurales mediante el software de análisis de estructuras de momentos. Los resultados indicaron que el nivel de estrés por la crianza y los síntomas depresivos de la madre estuvieron asociados con su propia calidez y crítica según la FMSS hacia el niño con TEA doce meses después en direcciones negativas y positivas. El nivel de estrés por la crianza de la madre también estuvo asociado negativamente con la calidez del padre según la FMSS hacia el niño con TEA doce meses después. Finalmente, el nivel de estrés por la crianza del padre estuvo asociado positivamente con su crítica según la FMSS hacia el niño con TEA. En general, los resultados indican que la relación entre la madre y el niño y la relación entre el padre y el niño están ambas influidas por el bienestar psicológico de los padres en las familias de niños con TEA; sin embargo, los efectos del actor son más fuertes para las madres y solo se encontraron efectos de la pareja para los padres. Se debaten las implicancias para las intervenciones.

Leisure activity in middle-aged adults with Down syndrome: Initiators, social partners, settings and barriers.

BACKGROUND: Leisure activity has been linked to optimal ageing outcomes, yet little is known about the type and level of leisure activity adults with Down syndrome currently engage in, and the factors that promote and hinder their leisure activities. MATERIALS AND METHODS: A daily diary was utilized to provide an in-depth description of the average daily leisure activity of 44 adults with Down syndrome (aged 25-56 years) across a typical 7-day period. Factors related to participation, including initiators, social partners, settings and barriers, were examined. RESULTS: Findings indicated that the majority of adults with Down syndrome did not meet established physical leisure activity intensity recommendations (i.e., 150 min/week moderately active activity) and did not exceed levels of passive leisure (e.g., watching television) found in the general population (i.e., 2-3 hr/day). Adults with Down syndrome self-initiated and self-engaged in the majority of their leisure activity. Family members and paid staff allocated resources towards initiating and engaging as social partners in social and physical leisure, respectively. CONCLUSIONS: Interventions and support services should partner with family members and paid staff to foster participation in adaptive leisure activity, perhaps through the establishment of leisure activity as part of daily routines.

Spillover of Marital Interactions and Parenting Stress in Families of Children With Autism Spectrum Disorder.

Few disorders appear to be more challenging for parents than autism spectrum disorder (ASD). Little is known about the extent to which parenting stress experienced by parents of children with ASD affects or is affected by marital quality. We examined daily spillover between level of parenting stress and marital interactions in a sample of 176 married couples (89.4% Caucasian, non-Hispanic) who have a child with ASD (5-12 years of age, 85% male) via a 14-day daily diary approach. On each day of the daily diary, parents individually reported on 8 positive and 8 negative marital interactions and their level of parenting stress. Dyadic multilevel modeling analyses using hierarchical linear modeling were conducted to examine same-day and lagged-effect associations between number of positive and negative marital interactions and level of parenting stress. Having a day with a higher number of negative marital interactions was associated with a higher level of parenting stress for both mothers and fathers of children with ASD. Having a day with fewer positive marital interactions was associated with having a more stressful parenting day for mothers of children with ASD. Same-day spillover was moderated by parent gender and the functioning of the child with ASD. Spillover flowed bidirectionally for mothers of children with ASD. Helping parents of children with ASD find ways to engage in positive marital interactions on stressful parenting days and avoid having negative affect, tension, and behaviors stemming from negative marital interactions spill into parenting experiences are important intervention targets.

Mothers' and Fathers' Prescription Drug Misuse in Family Contexts: Implications for the Adjustment of Parents of Children With and Without Autism.

Although prescription drug misuse is an identified risk factor for individuals' outcomes, less is known about its occurrence in and implications for families. To address this limitation, we examined whether mothers' and fathers' prescription drug misuse is associated with the adjustment of parents, including those with a child with autism spectrum disorder (ASD) and those without. Mothers and fathers from families with a child with ASD (n = 178) and comparison families without a child with ASD (n = 174) completed surveys of past-year prescription drug misuse and their personal and relationship adjustment. In total, 7.7% (N = 27) of mothers and 8.2% (N = 29) of fathers reported recent prescription drug misuse. There was significant interdependence between mothers' and fathers' recent prescription drug misuse in families with a child with ASD but not in comparison families. Actor-partner interdependence modeling was used to examine associations between parents' prescription drug misuse and their own and their partner's adjustment, controlling for medical use of prescription drugs and demographic covariates. Across family diagnosis statuses, mothers' prescription drug misuse predicted higher levels of their own alcohol problems, whereas fathers' prescription drug misuse related only to mothers' poorer sleep quality. Moreover, mothers' prescription drug misuse was associated with higher levels of their own depression symptoms in ASD-status (but not in comparison) families. Understanding parents' prescription drug misuse and its effects on family members is critical for informing future research and prevention and treatment strategies.

The effects of normal aging on amyloid-ß deposition in nondemented adults with Down syndrome as imaged by carbon 11-labeled Pittsburgh compound B.

INTRODUCTION: In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer-like neuropathology. METHODS: PET imaging with carbon 11-labeled Pittsburgh compound B examined the pattern of amyloid-ß deposition in 68 nondemented adults with DS (30-53 years) to determine the relationship between deposition and normal aging. Standard uptake value ratio (SUVR) images were created with cerebellar gray matter as the reference region. RESULTS: Multiple linear regression revealed slight but highly significant (corrected P < .05) positive correlations between SUVR and age. The striatum showed the strongest correlation, followed by precuneus, parietal cortex, anterior cingulate, frontal cortex, and temporal cortex. CONCLUSION: There is an age-related amyloid-ß deposition in the DS population, but as a pattern of elevated cortical retention becomes apparent, the correlation of SUVR with age ceases to be significant. Factors unrelated to aging may drive an increase in deposition during early Alzheimer's disease pathogenesis.

Cognitive functioning in relation to brain amyloid-ß in healthy adults with Down syndrome.

Nearly all adults with Down syndrome show neuropathology of Alzheimer's disease, including amyloid-ß deposition, by their fifth decade of life. In the current study, we examined the association between brain amyloid-ß deposition, assessed via in vivo assessments of neocortical Pittsburgh compound B, and scores on an extensive neuropsychological battery of measures of cognitive functioning in 63 adults (31 male, 32 female) with Down syndrome aged 30-53 years who did not exhibit symptoms of dementia. Twenty-two of the adults with Down syndrome were identified as having elevated neocortical Pittsburgh compound B retention levels. There was a significant positive correlation (r = 0.62, P < 0.0001) between age and neocortical Pittsburgh compound B retention. This robust association makes it difficult to discriminate normative age-related decline in cognitive functioning from any potential effects of amyloid-ß deposition. When controlling for chronological age in addition to mental age, there were no significant differences between the adults with Down syndrome who had elevated neocortical Pittsburgh compound B retention levels and those who did not on any of the neuropsychological measures. Similarly, when examining Pittsburgh compound B as a continuous variable, after controlling for mental age and chronological age, only the Rivermead Picture Recognition score was significantly negatively associated with neocortical Pittsburgh compound B retention. Our findings indicate that many adults with Down syndrome can tolerate amyloid-ß deposition without deleterious effects on cognitive functioning. However, we may have obscured true effects of amyloid-ß deposition by controlling for chronological age in our analyses. Moreover, our sample included adults with Down syndrome who were most 'resistant' to the effects of amyloid-ß deposition, as adults already exhibiting clinical symptoms of dementia symptoms were excluded from the study.

An Exploratory Study of Resilience to Stressful Life Events in Autistic Children.

Background: Autistic children experience more stressful life events (SLEs) than their neurotypical peers, which are related to poor mental health outcomes in both neurotypical and autistic individuals. However, there is a lack of longitudinal research assessing the perceived impact of stressful life events on autistic children's mental health. Method: Utilizing a novel statistical technique (Ratcliff et al., 2019), called 'area of resilience to stress events' or ARSE in R, we aimed to quantify aspects of resilience, growth, and non-resilience for 67 autistic children (6-13 years old) enrolled in a larger longitudinal study who experienced a SLE. Parents reported demographic information (e.g., child age, biological sex, household income) as well as the child's internalizing and externalizing symptoms and autism characteristics across multiple time points spaced one year apart (baseline, T2, T3, T4). Results: There was substantial variability in the resilience process within the sample. Older children exhibited a less adaptive resilience process (i.e., higher total scaled scores or arsets). Perceived stress of the disruptive event was not correlated with resilience; however, there was a significant child age x stress severity interaction, suggesting that younger children in households that perceived the disruptive event as highly stressful exhibited more efficient resilience, or lower arsets scores, compared to other children. Conclusions: This study introduces an innovative methodological approach to understanding the effects of stressful life events on the mental health of autistic children. Results have implications for family-based policy and practice and highlight for whom services may be most beneficial.

Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome.

INTRODUCTION: People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. METHODS: This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aß)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years). RESULTS: In general linear models lower plasma Aß42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. DISCUSSION: Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Highlights: Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease. METHODS: In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (18F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of amyloid. FINDINGS: We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease. INTERPRETATION: Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression. FUNDING: None.