Characterization of white matter hyperintensities in Down syndrome.

INTRODUCTION: In Down syndrome (DS), white matter hyperintensities (WMHs) are highly prevalent, yet their topography and association with sociodemographic data and Alzheimer's disease (AD) biomarkers remain largely unexplored. METHODS: In 261 DS adults and 131 euploid controls, fluid-attenuated inversion recovery magnetic resonance imaging scans were segmented and WMHs were extracted in concentric white matter layers and lobar regions. We tested associations with AD clinical stages, sociodemographic data, cerebrospinal fluid (CSF) AD biomarkers, and gray matter (GM) volume. RESULTS: In DS, total WMHs arose at age 43 and showed stronger associations with age than in controls. WMH volume increased along the AD continuum, particularly in periventricular regions, and frontal, parietal, and occipital lobes. Associations were found with CSF biomarkers and temporo-parietal GM volumes. DISCUSSION: WMHs increase 10 years before AD symptom onset in DS and are closely linked with AD biomarkers and neurodegeneration. This suggests a direct connection to AD pathophysiology, independent of vascular risks. HIGHLIGHTS: White matter hyperintensities (WMHs) increased 10 years before Alzheimer's disease symptom onset in Down syndrome (DS). WMHs were strongly associated in DS with the neurofilament light chain biomarker. WMHs were more associated in DS with gray matter volume in parieto-temporal areas.

Cross-sectional versus longitudinal cognitive assessments for the diagnosis of symptomatic Alzheimer's disease in adults with Down syndrome.

BACKGROUND: Down syndrome (DS) is a genetic form of Alzheimer's disease (AD). However, clinical diagnosis is difficult, and experts emphasize the need for detecting intra-individual cognitive decline. OBJECTIVE: To compare the performance of baseline and longitudinal neuropsychological assessments for the diagnosis of symptomatic AD in DS. METHODS: Longitudinal cohort study of adults with DS. Individuals were classified as asymptomatic, prodromal AD, or AD dementia. We performed receiver operating characteristic curve analyses to compare baseline and longitudinal changes of CAMCOG-DS and mCRT. RESULTS: We included 562 adults with DS. Baseline assessments showed good to excellent diagnostic performance for AD dementia (AUCs between 0.82 and 0.99) and prodromal AD, higher than the 1-year intra-individual cognitive decline (area under the ROC curve between 0.59 and 0.79 for AD dementia, lower for prodromal AD). Longer follow-ups increased the diagnostic performance of the intra-individual cognitive decline. DISCUSSION: Baseline cognitive assessment outperforms the 1-year intra-individual cognitive decline in adults with DS.

Basal forebrain atrophy along the Alzheimer's disease continuum in adults with Down syndrome.

BACKGROUND: Basal forebrain (BF) degeneration occurs in Down syndrome (DS)-associated Alzheimer's disease (AD). However, the dynamics of BF atrophy with age and disease progression, its impact on cognition, and its relationship with AD biomarkers have not been studied in DS. METHODS: We included 234 adults with DS (150 asymptomatic, 38 prodromal AD, and 46 AD dementia) and 147 euploid controls. BF volumes were extracted from T-weighted magnetic resonance images using a stereotactic atlas in SPM12. We assessed BF volume changes with age and along the clinical AD continuum and their relationship to cognitive performance, cerebrospinal fluid (CSF) and plasma amyloid/tau/neurodegeneration biomarkers, and hippocampal volume. RESULTS: In DS, BF volumes decreased with age and along the clinical AD continuum and significantly correlated with amyloid, tau, and neurofilament light chain changes in CSF and plasma, hippocampal volume, and cognitive performance. DISCUSSION: BF atrophy is a potentially valuable neuroimaging biomarker of AD-related cholinergic neurodegeneration in DS.

Metabolite Signature of Alzheimer's Disease in Adults with Down Syndrome.

OBJECTIVE: The purpose of this study was to examine the Alzheimer's disease metabolite signature through magnetic resonance spectroscopy in adults with Down syndrome and its relation with Alzheimer's disease biomarkers and cortical thickness. METHODS: We included 118 adults with Down syndrome from the Down Alzheimer Barcelona Imaging Initiative and 71 euploid healthy controls from the Sant Pau Initiative on Neurodegeneration cohort. We measured the levels of myo-inositol (a marker of neuroinflammation) and N-acetyl-aspartate (a marker of neuronal integrity) in the precuneus using magnetic resonance spectroscopy. We investigated the changes with age and along the disease continuum (asymptomatic, prodromal Alzheimer's disease, and Alzheimer's disease dementia stages). We assessed the relationship between these metabolites and Aß42 /Aß40 ratio, phosphorylated tau-181, neurofilament light (NfL), and YKL-40 cerebrospinal fluid levels as well as amyloid positron emission tomography uptake using Spearman correlations controlling for multiple comparisons. Finally, we computed the relationship between cortical thickness and metabolite levels using Freesurfer. RESULTS: Asymptomatic adults with Down syndrome had a 27.5% increase in the levels of myo-inositol, but equal levels of N-acetyl-aspartate compared to euploid healthy controls. With disease progression, myo-inositol levels increased, whereas N-acetyl-aspartate levels decreased in symptomatic stages of the disease. Myo-inositol was associated with amyloid, tau, and neurodegeneration markers, mainly at symptomatic stages of the disease, whereas N-acetyl-aspartate was related to neurodegeneration biomarkers in symptomatic stages. Both metabolites were significantly associated with cortical thinning, mainly in symptomatic participants. INTERPRETATION: Magnetic resonance spectroscopy detects Alzheimer's disease related inflammation and neurodegeneration, and could be a good noninvasive disease-stage biomarker in Down syndrome. ANN NEUROL 2021;90:407-416.

Amnestic and non-amnestic symptoms of dementia: An international study of Alzheimer's disease in people with Down's syndrome.

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.

The role of chronic physical exercise and selective attention at encoding on implicit and explicit memory.

Despite the evidence revealing benefits of chronic cardiovascular exercise on executive functions, little research has been conducted on long-term memory. We aimed to investigate the effect of physical exercise on implicit and explicit memory when attention was modulated at encoding in two groups of active and sedentary participants. With this purpose, attention was manipulated in a similar way in the implicit and explicit memory tasks by presenting picture outlines of two familiar objects, one in blue and the other in green, and participants were asked to pay attention only to one of them. Implicit memory was assessed through conceptual priming and explicit memory through a free recall task followed by recognition. The results did not reveal significant differences between groups in conceptual priming or free recall. However, in recognition, while both groups had similar discrimination for attended stimuli, active participants showed lower discrimination between unattended and new stimuli. These results suggested that exercise may have effects on specific cognitive processes, that is, that active participants may suppress non-relevant information better than sedentary participants, making the discrimination between unattended and new items more difficult.

Association of biological sex with clinical outcomes and biomarkers of Alzheimer's disease in adults with Down syndrome.

The study of sex differences in Alzheimer's disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer's disease (>90% in the 7th decade). Yet, sex differences in Alzheimer's disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer's disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-ß 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein ɛ4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein ɛ4, female ɛ4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein ɛ4 and biomarkers showed that female ɛ4 carriers tended to exhibit lower CSF amyloid-ß 42/amyloid-ß 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer's disease in adults with Down syndrome. Consideration of apolipoprotein ɛ4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine.

Neural correlates of episodic memory in adults with Down syndrome and Alzheimer's disease.

BACKGROUND: Adults with Down syndrome are at an ultra-high risk of developing early-onset Alzheimer's disease. Episodic memory deficits are one of the earliest signs of the disease, but their association with regional brain atrophy in the population with Down syndrome has not been explored. We aimed to investigate the neuroanatomical correlates of episodic memory in adults with Down syndrome and symptomatic Alzheimer's disease. METHODS: Single-center, cross-sectional study. A total of 139 adults with Down syndrome (85 asymptomatic and 54 with symptomatic Alzheimer's disease) were included in the study (mean age 43.6 ± 10.9 years, 46% female). Episodic memory was assessed using the modified Cued Recall Test. Immediate (trial 1 free immediate recall, trial 3 free immediate recall, total free immediate recall score, and total immediate score) and delayed scores (free delayed recall score and total delayed score) were examined. Cortical thickness from magnetic resonance imaging was determined with surface-based morphometry using the FreeSurfer 6.0 software package. The clusters of reduced cortical thickness were compared between symptomatic and asymptomatic participants to create a cortical atrophy map. Then, the correlation between cortical thickness and the modified Cued Recall Test subscores were separately assessed in symptomatic and asymptomatic subjects, controlling for age, sex, and severity of intellectual disability. RESULTS: Compared with asymptomatic participants, those with symptomatic Alzheimer's disease showed a pattern of cortical atrophy in posterior parieto-temporo-occipital cortices. In symptomatic subjects, trial 1 immediate free recall significantly correlated with cortical atrophy in lateral prefrontal regions. Trial 3 free immediate recall and total free immediate recall were associated with the most widespread cortical atrophy. Total immediate score was related to posterior cortical atrophy, including lateral parietal and temporal cortex, posterior cingulate cortex, precuneus, and medial temporal lobe areas. Delayed memory scores were associated with cortical atrophy in temporoparietal and medial temporal lobe regions. No significant relationships were observed between episodic memory measures and cortical atrophy in asymptomatic subjects. CONCLUSIONS: Different episodic memory measures were associated with cortical atrophy in specific brain regions in adults with Down syndrome and Alzheimer's disease. These results overlap with those described in sporadic Alzheimer's disease and further support the similarities between Down syndrome-associated Alzheimer's disease and that in the general population.

Longitudinal Clinical and Cognitive Changes Along the Alzheimer Disease Continuum in Down Syndrome.

Importance: Alzheimer disease (AD) is the main medical problem in adults with Down syndrome (DS). However, the associations of age, intellectual disability (ID), and clinical status with progression and longitudinal cognitive decline have not been established. Objective: To examine clinical progression along the AD continuum and its related cognitive decline and to explore the presence of practice effects and floor effects with repeated assessments. Design, Setting, and Participants: This is a single-center cohort study of adults (aged >18 years) with DS with different ID levels and at least 6 months of follow-up between November 2012 and December 2021. The data are from a population-based health plan designed to screen for AD in adults with DS in Catalonia, Spain. Individuals were classified as being asymptomatic, having prodromal AD, or having AD dementia. Exposures: Neurological and neuropsychological assessments. Main Outcomes and Measures: The main outcome was clinical change along the AD continuum. Cognitive decline was measured by the Cambridge Cognitive Examination for Older Adults With Down Syndrome and the modified Cued Recall Test. Results: A total of 632 adults with DS (mean [SD] age, 42.6 [11.4] years; 292 women [46.2%]) with 2847 evaluations (mean [SD] follow-up, 28.8 [18.7] months) were assessed. At baseline, there were 436 asymptomatic individuals, 69 patients with prodromal AD, and 127 with AD dementia. After 5 years of follow-up, 17.1% (95% CI, 12.5%-21.5%) of asymptomatic individuals progressed to symptomatic AD in an age-dependent manner (0.6% [95% CI, 0%-1.8%] for age <40 years; 21.1% [95% CI, 8.0%-32.5%] for age 40-44 years; 41.4% [95% CI, 23.1%-55.3%] for age 45-49 years; 57.5% [95% CI, 38.2%-70.8%] for age ≥50 years; P < .001), and 94.1% (95% CI, 84.6%-98.0%) of patients with prodromal AD progressed to dementia with no age dependency. Cognitive decline in the older individuals was most common among those who progressed to symptomatic AD and symptomatic individuals themselves. Importantly, individuals with mild and moderate ID had no differences in longitudinal cognitive decline despite having different performance at baseline. This study also found practice and floor effects, which obscured the assessment of longitudinal cognitive decline. Conclusions and Relevance: This study found an association between the development of symptomatic AD and a high risk of progressive cognitive decline among patients with DS. These results support the need for population health plans to screen for AD-related cognitive decline from the fourth decade of life and provide important longitudinal data to inform clinical trials in adults with DS to prevent AD.

Cortical atrophy and amyloid and tau deposition in Down syndrome: A longitudinal study.

Introduction: The Down syndrome population has a high prevalence for dementia, often showing their first clinical symptoms in their 40s. Methods: In a longitudinal cohort, we investigate whether amyloid deposition at time point 1 (TP1) could predict cortical thickness change at time point 2 (TP2). The association between tau burden and cortical thickness was also examined at time point 3 (TP3). Results: Between TP1 and TP2 there was pronounced cortical thinning in temporo-parietal cortices and cortical thickening in the frontal cortex. Baseline amyloid burden was strongly associated to cortical thinning progression, especially in the temporo-parietal regions. At TP3, tau deposition negatively correlated with cortical atrophy in regions where tau usually accumulates at later Braak stages. Discussion: A higher amount of amyloid accumulation triggers a cascade of changes of disease-causing processes that eventually lead to dementia. As expected, we found that regions where tau usually accumulates were those also displaying high levels of cortical atrophy.

Association of Alzheimer Disease With Life Expectancy in People With Down Syndrome.

Importance: People with Down syndrome have a high risk of developing Alzheimer disease dementia. However, penetrance and age at onset are considered variable, and the association of this disease with life expectancy remains unclear because of underreporting in death certificates. Objective: To assess whether the variability in symptom onset of Alzheimer disease in Down syndrome is similar to autosomal dominant Alzheimer disease and to assess its association with mortality. Design, Setting, and Participants: This study combines a meta-analysis with the assessment of mortality data from US death certificates (n = 77 347 case records with a International Classification of Diseases code for Down syndrome between 1968 to 2019; 37 900 [49%] female) and from a longitudinal cohort study (n = 889 individuals; 46% female; 3.2 [2.1] years of follow-up) from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI). Main Outcomes and Measures: A meta-analysis was conducted to investigate the age at onset, age at death, and duration of Alzheimer disease dementia in Down syndrome. PubMed/Medline, Embase, Web of Science, and CINAHL were searched for research reports, and OpenGray was used for gray literature. Studies with data about the age at onset or diagnosis, age at death, and disease duration were included. Pooled estimates with corresponding 95% CIs were calculated using random-effects meta-analysis. The variability in disease onset was compared with that of autosomal dominant Alzheimer disease. Based on these estimates, a hypothetical distribution of age at death was constructed, assuming fully penetrant Alzheimer disease. These results were compared with real-world mortality data. Results: In this meta-analysis, the estimate of age at onset was 53.8 years (95% CI, 53.1-54.5 years; n = 2695); the estimate of age at death, 58.4 years (95% CI, 57.2-59.7 years; n = 324); and the estimate of disease duration, 4.6 years (95% CI, 3.7-5.5 years; n = 226). Coefficients of variation and 95% prediction intervals of age at onset were comparable with those reported in autosomal dominant Alzheimer disease. US mortality data revealed an increase in life expectancy in Down syndrome (median [IQR], 1 [0.3-16] years in 1968 to 57 [49-61] years in 2019), but with clear ceiling effects in the highest percentiles of age at death in the last decades (90th percentile: 1990, age 63 years; 2019, age 65 years). The mortality data matched the limits projected by a distribution assuming fully penetrant Alzheimer disease in up to 80% of deaths (corresponding to the highest percentiles). This contrasts with dementia mentioned in 30% of death certificates but is in agreement with the mortality data in DABNI (78.9%). Important racial disparities persisted in 2019, being more pronounced in the lower percentiles (10th percentile: Black individuals, 1 year; White individuals, 30 years) than in the higher percentiles (90th percentile: Black individuals, 64 years; White individuals, 66 years). Conclusions and Relevance: These findings suggest that the mortality data and the consistent age at onset were compatible with fully penetrant Alzheimer disease. Lifespan in persons with Down syndrome will not increase until disease-modifying treatments for Alzheimer disease are available.

Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome.

Importance: Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE ɛ4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce. Objective: To investigate the association of the APOE ɛ4 allele with clinical and multimodal biomarkers of AD in adults with DS. Design, Setting, and Participants: This dual-center cohort study recruited adults with DS in Barcelona, Spain, and in Cambridge, UK, between June 1, 2009, and February 28, 2020. Included individuals had been genotyped for APOE and had at least 1 clinical or AD biomarker measurement; 2 individuals were excluded because of the absence of trisomy 21. Participants were either APOE ɛ4 allele carriers or noncarriers. Main Outcomes and Measures: Participants underwent a neurological and neuropsychological assessment. A subset of participants had biomarker measurements: Aß1-42, Aß1-40, phosphorylated tau 181 (pTau181) and neurofilament light chain (NfL) in cerebrospinal fluid (CSF), pTau181, and NfL in plasma; amyloid positron emission tomography (PET); fluorine 18-labeled-fluorodeoxyglucose PET; and/or magnetic resonance imaging. Age at symptom onset was compared between APOE ɛ4 allele carriers and noncarriers, and within-group local regression models were used to compare the association of biomarkers with age. Voxelwise analyses were performed to assess topographical differences in gray matter metabolism and volume. Results: Of the 464 adults with DS included in the study, 97 (20.9%) were APOE ɛ4 allele carriers and 367 (79.1%) were noncarriers. No differences between the 2 groups were found by age (median [interquartile range], 45.9 [36.4-50.2] years vs 43.7 [34.9-50.2] years; P = .56) or sex (51 male carriers [52.6%] vs 199 male noncarriers [54.2%]). APOE ɛ4 allele carriers compared with noncarriers presented with AD symptoms at a younger age (mean [SD] age, 50.7 [4.4] years vs 52.7 [5.8] years; P = .02) and showed earlier cognitive decline. Locally estimated scatterplot smoothing curves further showed between-group differences in biomarker trajectories with age as reflected by nonoverlapping CIs. Specifically, carriers showed lower levels of the CSF Aß1-42 to Aß1-40 ratio until age 40 years, earlier increases in amyloid PET and plasma pTau181, and earlier loss of cortical metabolism and hippocampal volume. No differences were found in NfL biomarkers or CSF total tau and pTau181. Voxelwise analyses showed lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume in APOE ɛ4 allele carriers. Conclusions and Relevance: In this study, the APOE ɛ4 allele was associated with earlier clinical and biomarker changes of AD in DS. These results provide insights into the mechanisms by which APOE increases the risk of AD, emphasizing the importance of APOE genotype for future clinical trials in DS.

Assessing general cognitive and adaptive abilities in adults with Down syndrome: a systematic review.

BACKGROUND: Measures of general cognitive and adaptive ability in adults with Down syndrome (DS) used by previous studies vary substantially. This review summarises the different ability measures used previously, focusing on tests of intelligence quotient (IQ) and adaptive behaviour (AB), and where possible examines floor effects and differences between DS subpopulations. We aimed to use information regarding existing measures to provide recommendations for individual researchers and the DS research community. RESULTS: Nineteen studies reporting IQ test data met inclusion for this review, with 17 different IQ tests used. Twelve of these IQ tests were used in only one study while five were used in two different studies. Eleven studies reporting AB test data met inclusion for this review, with seven different AB tests used. The only AB scales to be used by more than one study were the Vineland Adaptive Behaviour Scale (VABS; used by three studies) and the Vineland Adaptive Behavior Scale 2nd Edition (VABS-II; used by two studies). A variety of additional factors were identified which make comparison of test scores between studies problematic, including different score types provided between studies (e.g. raw scores compared to age-equivalent scores) and different participant inclusion criteria (e.g. whether individuals with cognitive decline were excluded). Floor effects were common for IQ tests (particularly for standardised test scores). Data exists to suggest that floor effects may be minimised by the use of raw test scores rather than standardised test scores. Raw scores may, therefore, be particularly useful in longitudinal studies to track change in cognitive ability over time. CONCLUSIONS: Studies assessing general ability in adults with DS are likely to benefit from the use of both IQ and AB scales. The DS research community may benefit from the development of reporting standards for IQ and AB data, and from the sharing of raw study data enabling further in-depth investigation of issues highlighted by this review.

Delineating the topography of amyloid-associated cortical atrophy in Down syndrome.

Older adults with Down syndrome (DS) often have Alzheimer's disease (AD) neuropathologies. Although positron emission tomography imaging studies of amyloid deposition (beta amyloid, Aß) have been associated with worse clinical prognosis and cognitive impairment, their relationships with cortical thickness remain unclear in people with DS. In a sample of 44 DS adults who underwent cognitive assessments, [11C]-PiB positron emission tomography, and T1-weighted magnetization-prepared rapid gradient echo, we used mixed effect models to evaluate the spatial relationships between Aß binding with patterns of cortical thickness. Partial Spearman correlations were used to delineate the topography of local Aß-associated cortical thinning. [11C]-PiB nondisplaceable binding potential was negatively associated with decreased cortical thickness. Locally, regional [11C]-PiB retention was negatively correlated with cortical thickness in widespread cortices, predominantly in temporoparietal regions. Contrary to the prevailing evidence in established AD, we propose that our findings implicate Aß in spatial patterns of atrophy that recapitulated the "cortical signature" of neurodegeneration in AD, conferring support to recent recommendations for earlier disease-interventions.

Longitudinal trajectories of amyloid deposition, cortical thickness, and tau in Down syndrome: A deep-phenotyping case report.

INTRODUCTION: Comorbid Alzheimer disease pathologies are frequently found in people with Down syndrome (DS). We report a deep phenotyping study undertaken over 7 years in a participant with DS who was nondemented at baseline but developed dementia after 5 years. METHODS: Throughout the course of the study, the participant was seen 4 times (2010, 2013, 2015, and 2017). Multimodal neuroimaging, including three serial scans of [11C]-PiB-PET, four structural magnetic resonance imagings, as well as a [18F]-AV1451 scan, was interpreted alongside detailed neuropsychological assessments over the study period. RESULTS: Amyloid beta accumulation preceded the onset of dementia and cognitive decline, which in turn corresponded to the predominant deposition of tau in temporoparietal cortices. DISCUSSION: Until now, data on the longitudinal trajectories of amyloid accumulation, tau pathology, and brain atrophy over multiple time points remain scarce in DS. This case report highlights the potential for deep phenotyping imaging to elucidate the substrates of cognitive decline in DS, although further longitudinal studies are necessary to clarify the relative contributions of both amyloid and tau.

Improving Memory Inhibition: A Study of Retrieval Induced Forgetting, Executive Control, and Chronic Aerobic Exercise.

Chronic aerobic exercise is being established as a way to enhance executive functions and prevent cognitive decline. In the current study, we are aiming to investigate whether chronic aerobic exercise would also modulate long-term memory retrieval under the context of the Retrieval Practice Paradigm. According to Anderson et al. (1994), the retrieval of relevant information may decrease the access to other related information inducing the failure to remember or forgetting Interestingly, it has been shown (Román et al., 2009) that this process is mediated by the level of attentional resources. In order to test if chronic aerobic exercise benefits attentional resources, we have applied the Dual Retrieval Practice Task. The purpose of this task is to evaluate the Retrieval Induced Forgetting (RIF) effect, which is supposed to index adaptive forgetting. More specifically, the Dual Retrieval Practice Task assesses the effects of memory retrieval on forgetting information directly related to the information that has been previously retrieved, but also studies the involvement of attentional resources on this type of forgetting (retrieval induced forgetting). This task alternates memory retrieval practice with an updating task in order to load attentional resources. Two groups of physically active and sedentary young participants were evaluated. The results showed that while active participants were able to show RIF despite the overload of the attentional resources, sedentary participants were not. These results are discussed in terms of the modulatory role of chronic aerobic exercise on executive control and retrieval induced forgetting.

Neuroimaging and other modalities to assess Alzheimer's disease in Down syndrome.

People with Down syndrome (DS) develop Alzheimer's disease (AD) at higher rates and a younger age of onset compared to the general population. As the average lifespan of people with DS is increasing, AD is becoming an important health concern in this group. Neuroimaging is becoming an increasingly useful tool in understanding the pathogenesis of dementia development in relation to clinical symptoms. Furthermore, neuroimaging has the potential to play a role in AD diagnosis and monitoring of therapeutics. This review describes major recent findings from in vivo neuroimaging studies analysing DS and AD via ligand-based positron emission tomography (PET), [18F] fluorodeoxyglucose (FDG)-PET, structural magnetic resonance imaging (sMRI), and diffusion tensor imaging (DTI). Electroencephalography (EEG) and retinal imaging are also discussed as emerging modalities. The review is organized by neuroimaging method and assesses the relationship between cognitive decline and neuroimaging changes. We find that amyloid accumulation seen on PET occurs prior to dementia onset, possibly as a precursor to the atrophy and white matter changes seen in MRI studies. Future PET studies relating tau distribution to clinical symptoms will provide further insight into the role this protein plays in dementia development. Brain activity changes demonstrated by EEG and metabolic changes seen via FDG-PET may also follow predictable patterns that can help track dementia progression. Finally, newer approaches such as retinal imaging will hopefully overcome some of the limitations of neuroimaging and allow for detection of dementia at an earlier stage.

Chronic exercise keeps working memory and inhibitory capacities fit.

Padilla et al. (2013) recently showed that chronic aerobic exercise in young adults is associated with better inhibitory control as measured by the strategic Stop Signal Task (SST). The aim of the current study was to explore whether better inhibitory abilities, associated with high levels of physical fitness, were also associated with higher working memory capacity (WMC) in young healthy adults. Participants aged between 18 and 30 years and showing different levels of fitness confirmed by the Rockport 1-mile walking fitness test took part in this study. Active and passive participants were administered the SST to measure inhibitory control, and the Automatic Operation Span (AOSPAN) to measure verbal WMC. We first replicated Padilla et al.'s results showing that exercise specifically modulates strategic inhibitory processes. Our results also showed that active participants presented with better WMC than sedentary ones, showing a better capacity to manage simultaneously two verbal tasks and to inhibit interference. The results point to an association between chronic exercise, inhibitory abilities, and WMC. The theoretical relationship between these variables will be discussed.

The effects of chronic exercise on attentional networks.

The aim of this study was to test the hypothesis that chronic physical exercise improves attentional control in young healthy participants. To do this, we compared the performance of physically active and passive participants in the Attentional Network Task, which allows for the assessment of the executive, orienting and alerting networks. The results showed a selective positive effect of exercise on the executive network. These results extend the evidence gathered in children, older adults and certain clinical populations suggesting that exercise can also improve attentional control in healthy young adults.

Analysis of the antibody structure based on high-resolution crystallographic studies.

High-resolution structures of liganded and unliganded antibody molecules were analyzed in terms of the interaction between the antibody with ligand, between the residues in the contact between the variable domains, and between the framework and the complementarity-determining regions of the antibody. The solvent accessibilities of the residues in the variable domains were also analyzed. The structural information is useful in the engineering of antibodies for therapeutic and other purposes.