Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma ...neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome.
We did a multicentre cohort study, including adults with Down syndrome (≥18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively; NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses.
Between Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia; ten 4% participants were excluded because their classification was uncertain. Mean follow-up was 3·6 years (SD 1·6, range 0·6–9·2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0·83 (95% CI 0·76–0·91) in the prodromal group and 0·94 (0·90–0·97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1·04-fold risk of clinical progression (95% CI 1·01–1·07; p=0·0034). Plasma NfL concentrations showed an annual increase of 3·0% (95% CI 0·4–5·8) per year in the asymptomatic non-progressors group, 11·5% (4·9–18·5) per year in the asymptomatic progressors group, and 16·0% (8·4–24·0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24·3% (15·3–34·1).
Plasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials.
AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, National Institute for Health Research, EU Joint Programme–Neurodegenerative Disease Research, Alzheimer's society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens und Umwelteinflüssen auf die menschliche Gesundheit, and NHS National Institute of Health Research Applied Research Collaborations East of England, UK.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Autistic people report difficulties with the demands of a neurotypical world, but little research has assessed the impact of the environment on such difficulties. We investigated the effect of ...ambient sounds on decision-making and heart rate variability. Adults without intellectual disability were allocated to autistic (n = 38) or neurotypical (n = 37) groups matched on age, intellectual functioning and self-reported gender. Participants completed a shopping decision-making task in three randomly ordered sound conditions: no sound, non-social shopping sound (e.g. fridges humming) and social shopping sound (e.g. people talking). Decision-making latency, decision-making consistency, and heart rate variability were measured. Participants also provided qualitative reports of their experiences. Qualitative analyses indicated that autistic participants experienced (1) the non-social and social sound conditions more negatively than the no sound condition and (2) the social sound condition more negatively than neurotypical participants. However, there were no statistically significant differences in decision-making latency, decision-making consistency, or heart rate variability across sound conditions and participant groups. Further research should consider alternative quantitative measures to explore subjective experience to help understand further which aspects of the environment autistic people are sensitive to, in turn, enabling more evidence-based autism-friendly changes to be made.
Lay abstract
Many autistic people report difficulties making decisions during everyday tasks, such as shopping. To examine the effect of sounds on decision-making, we developed a supermarket task where people watched a film shown from the shopper’s perspective and were asked to make decisions between different products. The task was divided into three sections and participants completed each section in a different auditory environment: (1) no sounds, (2) non-social sounds (e.g. fridges humming) and (3) social sounds (e.g. people talking). Thirty-eight autistic and 37 neurotypical adults took part. We measured decision-making by examining how long it took to make a decision and how consistent people were with their decisions. We also measured heart rate variability because this biological response provides a measure of anxiety. After the supermarket shopping task, participants told us in their own words about their experiences. Autistic participants said that they found the non-social and social sound conditions more difficult than the no sound condition, and autistic participants found the social sound condition more negative than neurotypical participants. However, decision-making and heart rate variability were similar for autistic and neurotypical participants across the sound conditions, suggesting that these measures may not have been sensitive enough to reflect the experiences the autistic participants reported. Further research should consider alternative measures to explore the experiences reported by autistic people to help us understand which specific aspects of the environment autistic people are sensitive to. This, in turn, may enable more specific and evidence-based autism-friendly changes to be made.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Autobiographical accounts and a limited research literature suggest that adults with autism spectrum disorders can experience difficulties with decision-making. We examined whether some of the ...difficulties they describe correspond to quantifiable differences in decision-making when compared to adults in the general population. The participants (38 intellectually able adults with autism spectrum disorders and 40 neurotypical adults) were assessed on three tasks of decision-making (Iowa Gambling Task, Cambridge Gamble Task and Information Sampling Task), which quantified, respectively, decision-making performance and relative attention to negative and positive outcomes, speed and flexibility, and information sampling. As a caution, all analyses were repeated with a subset of participants (nASD = 29 and nneurotypical = 39) who were not taking antidepressant or anxiolytic medication. Compared to the neurotypical participants, participants with autism spectrum disorders demonstrated slower decision-making on the Cambridge Gamble Task, and superior performance on the Iowa Gambling Task. When those taking the medications were excluded, participants with autism spectrum disorders also sampled more information. There were no other differences between the groups. These processing tendencies may contribute to the difficulties self-reported in some contexts; however, the results also highlight strengths in autism spectrum disorders, such as a more logical approach to, and care in, decision-making. The findings lead to recommendations for how adults with autism spectrum disorders may be better supported with decision-making.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Autobiographical and clinical accounts, as well as a limited neuropsychological research literature, suggest that, in some situations, men and women with autism spectrum conditions (ASCs) may have ...difficulty making decisions. Little is known, however, about how people with ASCs experience decision-making or how they might best be supported to make decisions for themselves. In this study, we compared the decision-making experiences of adults with and without ASCs (n=38 and n=40, respectively) using a novel questionnaire and the General Decision Making Style inventory (GDMS, Scott & Bruce, 1995). The participants with ASCs reported experiencing several problems in decision-making more frequently than the comparison group, and were more likely to report avoidance of decision-making, as measured using the GDMS. The findings highlight areas of potential future research and inform suggestions for supporting adults with ASCs during decision-making
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Down's syndrome is associated with pathological ageing and a propensity for early‐onset Alzheimer's disease. The early symptoms of dementia in people with Down's syndrome may reflect frontal lobe ...vulnerability to amyloid deposition. Auditory predictive processes rely on the bilateral auditory cortices with the recruitment of frontal cortices and appear to be impaired in pathologies characterized by compromised frontal lobe. Hence, auditory predictive processes were investigated to assess Down's syndrome pathology and its relationship with pathological ageing. An auditory electroencephalography (EEG) global–local paradigm was presented to the participants, in which oddball stimuli could either violate local or higher level global rules. We characterised predictive processes in individuals with Down's syndrome and their relationship with pathological ageing, with a focus on the EEG event‐related potential called Mismatch Negativity (MMN) and the P300. In Down's syndrome, we also evaluated the EEG components as predictor of cognitive decline 1 year later. We found that predictive processes of detection of auditory violations are overall preserved in Down's syndrome but also that the amplitude of the MMN to local deviancies decreases with age. However, the 1‐year follow‐up of Down's syndrome found that none of the ERPs measures predicted subsequent cognitive decline. The present study provides a novel characterization of electrophysiological markers of local and global predictive processes in Down's syndrome.
Down's syndrome (DS) is associated with pathological ageing characterised by early frontocentral impairment. We characterised frontocentral electrophysiological markers of local and global auditory prediction processes in DS. We assessed whether those markers may inform on pathological ageing in DS. Detection of local and global violations appears to be preserved in DS. The amplitude of the MMN elicited by local auditory violations was also a predictor of age in DS but not in controls.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
Posterior fossa brain tumours (PFT) and their treatment in young children are often associated with subsequent cognitive impairment. However, reported follow-up periods rarely exceed ...10 years. This study reports very long-term cognitive consequences of surviving an early childhood PFT.
Methods
62 adult survivors of a PFT, ascertained from a national register, diagnosed before 5 years of age, and a sibling control, received a single IQ assessment an average of 32 years (range 18–53) after initial diagnosis, using the Weschler Abbreviated Scale of Intelligence. Regression models were fitted to survivor–sibling pair differences on verbal and performance IQ (VIQ and PIQ) scores to investigate whether increasing time between PFT diagnosis and follow-up IQ assessment contributed to survivor–sibling IQ differences.
Results
At follow-up, survivors had, on average, VIQ 15 points and PIQ 19 points lower than their siblings. There was no significant effect of time since diagnosis on survivor–sibling VIQ difference. Survivors who received radiotherapy showed no significant effect of time since diagnosis on survivor–sibling PIQ difference. Survivors who did not receive radiotherapy demonstrated a trend for it to reduce.
Conclusions
VIQ and PIQ deficits persist in adulthood, suggesting the effect of a fixed injury imposing on cognitive development, rather than an ongoing pathological process.
Implications for cancer survivors
The findings will help parents and others supporting survivors of an early life PFT to identify and plan for possible cognitive outcomes, and highlight the importance of early interventions to optimize cognitive function during the developmental period.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objectives
To understand the views of qualified medical practitioners regarding “reasonable adjustments” and the quality of the care and treatment provided to adults with intellectual disabilities ...when admitted to acute hospitals as inpatients.
Methods
Semi‐structured interviews took place with 14 medical practitioners, seven from each of two acute hospitals, with a thematic analysis of the resulting data.
Results
All 14 medical practitioners reported problems in the diagnosis and treatment of patients with intellectual disabilities. Most participants attributed these difficulties to communication problems and/or behaviours that, in the context of a hospital ward, were non‐conforming. However, a minority reported that, because they were likely to have multiple comorbid health conditions, patients with intellectual disabilities were more complex. In addition, half of all these respondents reported making little use of “reasonable adjustments” introduced to improve the quality of the care received by this group of patients.
Conclusions
Medical practitioners should make better use of the “reasonable adjustments” introduced in the UK to address inequities in care and treatment received by patients with intellectual disabilities. However, training should also focus on the biomedical complexities often presented by these men and women.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
•Longitudinal analysis of tau and amyloid-β interaction in Down syndrome.•Tau as an independent predictor of cognitive and functional change.•Tau as a better predictor of cognitive and functional ...change than amyloid-β status.•Evidence that tau and amyloid-β contribute synergistically to cognitive decline.
This study investigates whether tau has (i) an independent effect from amyloid-β on changes in cognitive and functional performance and (ii) a synergistic relationship with amyloid-β in the exacerbation of decline in aging Down syndrome (DS).
105 participants with DS underwent baseline PET 18F-AV1451 and PET 11CPiB scans to quantify tau deposition in Braak regions II-VI and the Striatum and amyloid-β status respectively. Linear Mixed Effects models were implemented to assess how tau and amyloid-β deposition are related to change over three time points.
Tau was a significant independent predictor of cognitive and functional change. The three-way interaction between time, 11CPiB status and tau was significant in the models of episodic memory and visuospatial cognition.
Baseline tau is a significant predictor of cognitive and functional decline, over and above the effect of amyloid-β status. Results suggest a synergistic relationship between amyloid-β status and tau as predictors of change in memory and visuospatial cognition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The purpose of this review is to compare and highlight the clinical and pathological aspects of genetic versus acquired Alzheimer's disease: Down syndrome-associated Alzheimer's disease in (DSAD) and ...Autosomal Dominant Alzheimer's disease (ADAD) are compared with the late-onset form of the disease (LOAD). DSAD and ADAD present in a younger population and are more likely to manifest with non-amnestic (such as dysexecutive function features) in the prodromal phase or neurological features (such as seizures and paralysis) especially in ADAD. The very large variety of mutations associated with ADAD explains the wider range of phenotypes. In the LOAD, age-associated comorbidities explain many of the phenotypic differences.
The presence of age‐related neuropathology characteristic of Alzheimer's disease (AD) in people with Down syndrome (DS) is well‐established. However, the early symptoms of dementia may be atypical ...and appear related to dysfunction of prefrontal circuitry.
Objective
To characterize the initial informant reported age‐related neuropsychiatric symptoms of dementia in people with DS, and their relationship to AD and frontal lobe function.
Methods
Non‐amnestic informant reported symptoms (disinhibition, apathy, and executive dysfunction) and amnestic symptoms from the CAMDEX‐DS informant interview were analyzed in a cross‐sectional cohort of 162 participants with DS over 30 years of age, divided into three groups: stable cognition, prodromal dementia, and AD. To investigate age‐related symptoms prior to evidence of prodromal dementia we stratified the stable cognition group by age.
Results
Amnestic and non‐amnestic symptoms were present before evidence of informant‐reported cognitive decline. In those who received the diagnosis of AD, symptoms tended to be more marked. Memory impairments were more marked in the prodromal dementia than the stable cognition group (OR = 35.07; P < .001), as was executive dysfunction (OR = 7.16; P < .001). Disinhibition was greater in the AD than in the prodromal dementia group (OR = 3.54; P = .04). Apathy was more pronounced in the AD than in the stable cognition group (OR = 34.18; P < .001).
Conclusion
Premorbid amnestic and non‐amnestic symptoms as reported by informants increase with the progression to AD. For the formal diagnosis of AD in DS this progression of symptoms needs to be taken into account. An understanding of the unique clinical presentation of DS in AD should inform treatment options.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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