RESUMO
Prior authorization criteria for Federal Drug Administration (FDA) approved immunotherapeutics, among the class of anti-amyloid monoclonal antibodies (mAbs), established by state drug formulary committees, are tailored for adults with late-onset Alzheimer's disease. This overlooks adults with Down syndrome (DS), who often experience dementia at a younger age and with different diagnostic assessment outcomes. This exclusion may deny DS adults access to potential disease-modifying treatments. To address this issue, an international expert panel convened to establish adaptations of prescribing criteria suitable for DS patients and parameters for access to Centers for Medicare & Medicaid Services (CMS) registries. The panel proposed mitigating disparities by modifying CMS and payer criteria to account for younger onset age, using alternative language and assessment instruments validated for cognitive decline in the DS population. The panel also recommended enhancing prescribing clinicians' diagnostic capabilities for DS and initiated awareness-raising activities within healthcare organizations. These efforts facilitated discussions with federal officials, aimed at achieving equity in access to anti-amyloid immunotherapeutics, with implications for national authorities worldwide evaluating these and other new disease-modifying therapeutics for Alzheimer's disease.
Assuntos
Síndrome de Down , Humanos , Estados Unidos , Doença de Alzheimer/tratamento farmacológico , Adulto , Anticorpos Monoclonais/uso terapêutico , Imunoterapia/métodosRESUMO
INTRODUCTION: Adults with Down syndrome, the largest population genetically predisposed to high risk for Alzheimer's disease (AD), are ideally suited participants for clinical trials targeting prevention. Critically important considerations for the design of such trials include appropriate selection of participants, outcome measures, and duration of follow-up. METHODS: Archived data for 12 measures of performance over a 3-year period were analyzed for 185 adults with Down syndrome 36 years of age and older with presumptive preclinical AD. RESULTS: Declines over 3 years were not observed prior to 46 years of age. However, declines were observed at older ages, increasing monotonically for groups aged 46-49, 50-55, and >55, as did incidence of prodromal AD and dementia. DISCUSSION: Significant decline over a 2- to 3-year period for a prospective placebo group of adults with Down syndrome enrolled in clinical prevention trials can only be expected when inclusion is limited to adults older than 45 years of age.
Assuntos
Doença de Alzheimer , Síndrome de Down , Adulto , Humanos , Pessoa de Meia-Idade , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/prevenção & controle , Síndrome de Down/epidemiologia , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Cerebrovascular disease is associated with symptoms and pathogenesis of Alzheimer's disease (AD) among adults with Down syndrome (DS). The cause of increased dementia-related cerebrovascular disease in DS is unknown. We explored whether protein markers of neuroinflammation are associated with markers of cerebrovascular disease among adults with DS. Participants from the Alzheimer's disease in Down syndrome (ADDS) study with magnetic resonance imaging (MRI) scans and blood biomarker data were included. Support vector machine (SVM) analyses examined the relationship of blood-based proteomic biomarkers with MRI-defined cerebrovascular disease among participants characterized as having cognitive decline (n = 36, mean age ± SD = 53 ± 6.2) and as being cognitively stable (n = 78, mean age = 49 ± 6.4). Inflammatory and AD markers were associated with cerebrovascular disease, particularly among symptomatic individuals. The pattern suggested relatively greater inflammatory involvement among cognitively stable individuals and greater AD involvement among those with cognitively decline. The findings help to generate hypotheses that both inflammatory and AD markers are implicated in cerebrovascular disease among those with DS and point to potential mechanistic pathways for further examination.
Assuntos
Doença de Alzheimer , Transtornos Cerebrovasculares , Síndrome de Down , Adulto , Humanos , Pessoa de Meia-Idade , Doença de Alzheimer/patologia , Síndrome de Down/patologia , Proteoma , Proteômica , Transtornos Cerebrovasculares/complicações , BiomarcadoresRESUMO
OBJECTIVE: Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status. METHODS: Participants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status. RESULTS: There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct. INTERPRETATION: The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165-1177.
Assuntos
Doença de Alzheimer/patologia , Amiloide/metabolismo , Transtornos Cerebrovasculares/patologia , Síndrome de Down/patologia , Hemorragia/patologia , Hipertrofia/patologia , Infarto/patologia , Substância Branca/patologia , Doença de Alzheimer/complicações , Transtornos Cerebrovasculares/complicações , Disfunção Cognitiva/complicações , Disfunção Cognitiva/patologia , Síndrome de Down/complicações , Feminino , Hemorragia/complicações , Humanos , Hipertrofia/complicações , Infarto/complicações , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: The accuracy of the National Task Group-Early Detection Screen for Dementia (NTG-EDSD) was evaluated in a sample of 185 adults with Down syndrome (DS), emphasizing 'mild cognitive impairment (MCI-DS)'. METHOD: Knowledgeable informants were interviewed with the NTG-EDSD, and findings were compared to an independent dementia status rating based on consensus review of detailed assessments of cognition, functional abilities and health status (including physician examination). RESULTS: Results indicated that sections of the NTG-EDSD were sensitive to MCI-DS, with one or more concerns within the 'Memory' or 'Language and Communication' domains being most informative. CONCLUSIONS: The NTG-EDSD is a useful tool for evaluating dementia status, including MCI-DS. However, estimates of sensitivity and specificity, even for detecting frank dementia, indicated that NTG-EDSD findings need to be supplemented by additional sources of relevant information to achieve an acceptable level of diagnostic/screening accuracy.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Síndrome de Down , Deficiência Intelectual , Adulto , Disfunção Cognitiva/diagnóstico , Progressão da Doença , Síndrome de Down/diagnóstico , Humanos , Testes NeuropsicológicosRESUMO
Telomere shortening was shown to parallel Alzheimer's disease (AD) associated dementia. By using a dual PNA Probe system we have developed a practical method for comparing telomere length in T-lymphocyte interphases from individuals with Down syndrome (DS) with and without "mild cognitive impairment" (MCI-DS) and demonstrated that telomere length can serve as a valid biomarker for the onset of MCI-DS in this high-risk population. To verify progressive cognitive decline we have now examined sequential changes in telomere length in 10 adults with DS (N = 4 Female, N = 6 Male) developing MCI-DS. Cases were selected blind to telomere length from a sample of adults with DS previously enrolled in a prospective longitudinal study at 18-month intervals with clinical and telomere assessments: (1) MCI-DS group data were collected approximately three years prior to development of MCI-DS; (2) 18 months later; (3) when MCI-DS was first observed. These telomere measures were compared to those from another 10 adults with DS matched by sex and approximate age but without indications of MCI-DS (Controls). PNA (peptide nucleic acid) probes for telomeres together with a chromosome two centromere probe were used. Findings indicated telomere shortening over time for both Cases and Controls. Group differences emerged by 18-months prior to recognition of MCI-DS onset and completely non-overlapping distributions of telomere measures were observed by the time of MCI-DS onset. This study adds to accumulating evidence of the value of telomere length, as an early biomarker of AD progression in adults with Down syndrome.
Assuntos
Doença de Alzheimer/patologia , Biomarcadores/análise , Disfunção Cognitiva/patologia , Síndrome de Down/patologia , Encurtamento do Telômero , Adulto , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Disfunção Cognitiva/complicações , Disfunção Cognitiva/genética , Progressão da Doença , Síndrome de Down/complicações , Síndrome de Down/genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Previous studies have suggested that Alzheimer's disease (AD) causes an accelerated shortening of telomeres, the ends of chromosomes consisting of highly conserved TTAGGG repeats that, because of unidirectional 5'-3' DNA synthesis, lose end point material with each cell division. Our own previous work suggested that telomere length of T-lymphocytes might be a remarkably accurate biomarker for "mild cognitive impairment" in adults with Down syndrome (MCI-DS), a population at dramatically high risk for AD. To verify that the progression of cognitive and functional losses due to AD produced this observed telomere shortening, we have now examined sequential changes in telomere length in five individuals with Down syndrome (3F, 2M) as they transitioned from preclinical AD to MCI-DS (N = 4) or dementia (N = 1). As in our previous studies, we used PNA (peptide nucleic acid) probes for telomeres and the chromosome 2 centromere (as an "internal standard" expected to be unaffected by aging or dementia status), with samples from the same individuals now collected prior to and following development of MCI-DS or dementia. Consistent shortening of telomere length was observed over time. Further comparisons with our previous cross-sectional findings indicated that telomere lengths prior to clinical decline were similar to those of other adults with Down syndrome (DS) who have not experienced clinical decline while telomere lengths following transition to MCI-DS or dementia in the current study were comparable to those of other adults with DS who have developed MCI-DS or dementia. Taken together, findings indicate that telomere length has significant promise as a biomarker of clinical progression of AD for adults with DS, and further longitudinal studies of a larger sample of individuals with DS are clearly warranted to validate these findings and determine if and how factors affecting AD risk also influence these measures of telomere length.
Assuntos
Demência/complicações , Demência/genética , Síndrome de Down/complicações , Síndrome de Down/genética , Encurtamento do Telômero/genética , Adulto , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Metáfase/genética , Pessoa de Meia-Idade , Linfócitos T/metabolismoRESUMO
In the United States, estimates indicate there are between 250,000 and 400,000 individuals with Down syndrome (DS), and nearly all will develop Alzheimer's disease (AD) pathology starting in their 30s. With the current lifespan being 55 to 60 years, approximately 70% will develop dementia, and if their life expectancy continues to increase, the number of individuals developing AD will concomitantly increase. Pathogenic and mechanistic links between DS and Alzheimer's prompted the Alzheimer's Association to partner with the Linda Crnic Institute for Down Syndrome and the Global Down Syndrome Foundation at a workshop of AD and DS experts to discuss similarities and differences, challenges, and future directions for this field. The workshop articulated a set of research priorities: (1) target identification and drug development, (2) clinical and pathological staging, (3) cognitive assessment and clinical trials, and (4) partnerships and collaborations with the ultimate goal to deliver effective disease-modifying treatments.
Assuntos
Doença de Alzheimer/fisiopatologia , Síndrome de Down/fisiopatologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Ensaios Clínicos como Assunto , Congressos como Assunto , Modelos Animais de Doenças , Síndrome de Down/diagnóstico , Síndrome de Down/tratamento farmacológico , Síndrome de Down/patologia , Descoberta de Drogas , Humanos , Testes NeuropsicológicosRESUMO
BACKGROUND: In individuals with Down syndrome, virtually all structures of the eye have some abnormality, which likely diminishes vision. We examined basic vision functions in adults with Down syndrome. MATERIALS AND METHODS: Participants completed a battery of psychophysical tests that probed a comprehensive array of visual functions. The performance of adults with Down syndrome was compared with younger and older adults without intellectual disability. RESULTS: Adults with Down syndrome had significant vision deficits, reduced sensitivity across spatial frequencies and temporal modulation rates, reduced stereopsis, impaired vernier acuity and anomalies in colour discrimination. The pattern of deficits observed was similar to those seen by researchers examining adults with Alzheimer's disease. CONCLUSIONS: Our findings suggest that a common mechanism may be responsible for the pattern of deficits observed, possibly the presence of Alzheimer's disease neuropathology in the visual association cortex. We also showed that individuals with mild to moderate intellectual disability are capable of participating in studies employing state-of-the-art psychophysical procedures. This has wider implications in terms of their ability to participate in research that use similar techniques.
Assuntos
Síndrome de Down/fisiopatologia , Transtornos da Visão/diagnóstico , Testes Visuais/métodos , Adulto , Visão de Cores/fisiologia , Sensibilidades de Contraste/fisiologia , Percepção de Profundidade/fisiologia , Síndrome de Down/complicações , Humanos , Pessoa de Meia-Idade , Psicofísica/instrumentação , Psicofísica/métodos , Distribuição Aleatória , Transtornos da Visão/etiologia , Testes Visuais/instrumentação , Acuidade Visual/fisiologia , Adulto JovemRESUMO
INTRODUCTION: Alzheimer's disease (AD) affecting adults with Down syndrome (DS-AD), like late-onset AD (LOAD) in the neurotypical population, has preclinical, prodromal, and more advanced stages. Only tasks placing high demands on cognition are expected to be affected during the prodromal stage, with activities of daily living (ADLs) typically being spared. However, cognitive demands of ADLs could be high for adults with DS and may be affected during prodromal DS-AD. METHODS: Cognitively stable cases that subsequently developed prodromal DS-AD were identified within a set of archived data from a previous longitudinal study. Measures of ADLs and multiple cognitive domains were examined over time. RESULTS: Clear declines in ADLs accompanied cognitive declines with prodromal DS-AD while stability in all measures was verified during preclinical DS-AD. DISCUSSION: Operationally defining prodromal DS-AD is essential to disease staging in this high-risk population and for informing treatment options and timing as new disease-modifying drugs become available. Highlights: Cognitive and functional stability were demonstrated prior to the onset of prodromal DS-AD.ADL declines accompanied cognitive declines as adults with DS transitioned to prodromal AD.Declines in ADLs should be a defining feature of prodromal AD for adults with DS.Better characterization of prodromal DS-AD can improve AD diagnosis and disease staging.Improvements in DS-AD diagnosis and staging could also inform the timing of interventions.
RESUMO
INTRODUCTION: Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimer's disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS. METHODS: T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory. RESULTS: Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory. DISCUSSION: The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS.
RESUMO
Adults with Down syndrome are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with Down syndrome via structural imaging markers of cerebrovascular disease and atrophy. The study included participants with Down syndrome from the Alzheimer's Disease - Down Syndrome study (n = 195, age = 50.6 ± 7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal and occipital white matter hyperintensity volume but not with enlarged perivascular spaces, microbleeds or infarcts. Using a structural equation model, we found that pulse pressure was associated with greater white matter hyperintensity volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension.
RESUMO
The chromosome 21 gene RCAN1, encoding a modulator of the calcineurin (CaN) phosphatase, is a candidate gene for contributing to cognitive disability in people with Down syndrome (DS; trisomy 21). To develop a physiologically relevant model for studying the biochemistry of RCAN1 and its contribution to DS, we generated bacterial artificial chromosome-transgenic (BAC-Tg) mouse lines containing the human RCAN1 gene with a C-terminal HA-FLAG epitope tag incorporated by recombineering. The BAC-Tg was expressed at levels only moderately higher than the native Rcan1 gene: approximately 1.5-fold in RCAN1 (BAC-Tg1) and twofold in RCAN1 (BAC-Tg2). Affinity purification of the RCAN1 protein complex from brains of these mice revealed a core complex of RCAN1 with CaN, glycogen synthase kinase 3-beta (Gsk3b), and calmodulin, with substoichiometric components, including LOC73419. The BAC-Tg mice are fully viable, but long-term synaptic potentiation is impaired in proportion to BAC-Tg dosage in hippocampal brain slices from these mice. RCAN1 can act as a tumor suppressor in some systems, but we found that the RCAN1 BAC-Tg did not reduce mammary cancer growth when present at a low copy number in Tp53;WAP-Cre mice. This work establishes a useful mouse model for investigating the biochemistry and dose-dependent functions of the RCAN1 protein in vivo.
Assuntos
Cromossomos Artificiais Bacterianos/genética , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos Transgênicos , Proteínas Musculares/genética , Animais , Encéfalo/metabolismo , Calcineurina/genética , Calcineurina/metabolismo , Células Cultivadas , Cromossomos/genética , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Síndrome de Down/genética , Feminino , Dosagem de Genes , Loci Gênicos , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células Jurkat , Estimativa de Kaplan-Meier , Potenciação de Longa Duração/genética , Masculino , Camundongos , Proteínas Musculares/metabolismo , Neurônios/citologia , Neurônios/metabolismoRESUMO
The primary abnormality in Down syndrome (DS), trisomy 21, is well known; but how this chromosomal gain produces the complex DS phenotype, including immune system defects, is not well understood. We profiled DNA methylation in total peripheral blood leukocytes (PBL) and T-lymphocytes from adults with DS and normal controls and found gene-specific abnormalities of CpG methylation in DS, with many of the differentially methylated genes having known or predicted roles in lymphocyte development and function. Validation of the microarray data by bisulfite sequencing and methylation-sensitive Pyrosequencing (MS-Pyroseq) confirmed strong differences in methylation (p<0.0001) for each of 8 genes tested: TMEM131, TCF7, CD3Z/CD247, SH3BP2, EIF4E, PLD6, SUMO3, and CPT1B, in DS versus control PBL. In addition, we validated differential methylation of NOD2/CARD15 by bisulfite sequencing in DS versus control T-cells. The differentially methylated genes were found on various autosomes, with no enrichment on chromosome 21. Differences in methylation were generally stable in a given individual, remained significant after adjusting for age, and were not due to altered cell counts. Some but not all of the differentially methylated genes showed different mean mRNA expression in DS versus control PBL; and the altered expression of 5 of these genes, TMEM131, TCF7, CD3Z, NOD2, and NPDC1, was recapitulated by exposing normal lymphocytes to the demethylating drug 5-aza-2'deoxycytidine (5aza-dC) plus mitogens. We conclude that altered gene-specific DNA methylation is a recurrent and functionally relevant downstream response to trisomy 21 in human cells.
Assuntos
Metilação de DNA/genética , Síndrome de Down/genética , Leucócitos/metabolismo , Adulto , Envelhecimento/genética , Azacitidina/farmacologia , Criança , Pré-Escolar , Metilação de DNA/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lactente , Células Jurkat , Contagem de Leucócitos , Leucócitos/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Análise de Sequência de DNA , SulfitosRESUMO
Introduction: Adults with Down syndrome (DS) are at increased risk for Alzheimer's disease (AD) and vary in their age of transition from AD preclinical to prodromal or more advanced clinical stages. An empirically based method is needed to determine individual "estimated years from symptom onset (EYO)," the same construct used in studies of autosomal dominant AD . Methods: Archived data from a previous study of > 600 adults with DS were examined using survival analysis methods. Age-specific prevalence of prodromal AD or dementia, cumulative risk, and EYOs were determined. Results: Individualized EYOs for adults with DS ranging in age from 30 to 70+ were determined, dependent upon chronological age and clinical status. Discussion: EYOs can be a useful tool for studies focused on biomarker changes during AD progression in this and other populations at risk, studies that should contribute to improved methods for diagnosis, prediction of risk, and identification of promising treatment targets. HIGHLIGHTS: Years from Alzheimer's disease (AD) onset (EYO) was estimated for adults with Down syndrome (DS).EYOs were informed by AD clinical status and age, ranging from 30 to > 70 years.Influences of biological sex and apolipoprotein E genotype on EYOs were examined.EYOs have advantages for predicting risk of AD-related dementia compared to age.EYOs can be extremely informative in studies of preclinical AD progression.
RESUMO
Individuals with Down syndrome (DS) are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease, entorhinal cortical atrophy, and diagnosis of dementia in adults with DS. Participants with DS from the Biomarkers of Alzheimer's Disease in Adults with Down Syndrome study (ADDS; n=195, age=50.6±7.2 years, 44% women, 18% diagnosed with dementia) were included. Higher pulse pressure was associated with greater global, parietal, and occipital WMH volume. Pulse pressure was not related to enlarged PVS, microbleeds, infarcts, entorhinal cortical thickness, or dementia diagnosis. However, in a serial mediation model, we found that pulse pressure was indirectly related to dementia diagnosis through parieto-occipital WMH and, subsequently through entorhinal cortical thickness. Higher pulse pressure may be a risk factor for dementia in people with DS by promoting cerebrovascular disease, which in turn affects neurodegeneration. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension.
RESUMO
BACKGROUND: Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people. METHODS: In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid ß42 (Aß42) to Aß40 (Aß42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE É4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aß42/40 was evaluated. FINDINGS: 192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aß42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p<0·0001) and in people with Down syndrome (n=32; r=-0·801; p<0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE É4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset -23·0 vs -17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome. INTERPRETATION: Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome. FUNDING: The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Córtex Cerebral , Síndrome de Down , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/análise , Apolipoproteínas E/genética , Biomarcadores/análise , Estudos Transversais , Síndrome de Down/sangue , Síndrome de Down/diagnóstico por imagem , Síndrome de Down/genética , Tomografia por Emissão de Pósitrons , Córtex Cerebral/química , Córtex Cerebral/diagnóstico por imagemRESUMO
We have observed evidence of increased telomere shortening in short-term T-lymphocyte cultures following freezing and thawing of the original inoculum obtained by ficoll-paque gradient centrifugation, compared to T-lymphocytes that were cultured immediately without freezing and thawing from the same blood sample from 3 female and 3 male adults. Because freezing may have similar effects on other cell types, and because telomere shortening may only manifest its effects after many years or decades, we suggest there is a pressing need for evaluation of the effects of freezing on any cells envisioned for clinical applications, including embryo implantation.
Assuntos
Encurtamento do Telômero , Telômero/fisiologia , Adulto , Idoso , Feminino , Congelamento , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Linfócitos T/metabolismo , Telômero/genética , Telômero/metabolismoRESUMO
Previously, we established that short-term T lymphocyte cultures from people with Down syndrome (DS) and dementia (Alzheimer's disease) had shorter telomeres than did those from age- and sex-matched people with DS only, quantified as significantly reduced numbers of signals of peptide nucleic acid (PNA) telomere probes in whole metaphases [Jenkins et al. (2008); Neurosci Lett 440:340-343] as well as reduced telomere probe light intensity values in interphases [Jenkins et al. (2010); Neurobiol Aging 31:765-771]. We now describe shorter telomere length in adults with DS and mild cognitive impairment (MCI) compared to age- and sex-matched individuals with DS without MCI. Telomere length is quantified by reduced telomere signal numbers and shorter chromosome 1 telomeres measured in micrometers (microns). These findings were in agreement with quantitative light intensity measurements of chromosome 1 and chromosome 21 PNA telomere probes with and without the use of a "normalizing ratio" involving the fluorescence exhibited by a PNA probe for centromere 2, and with the use of light intensity measurements of interphase preparations. Most importantly, the distributions of chromosome 1 telomere lengths (in microns) were completely non-overlapping for adults with and without MCI, indicating that this measure has great promise as a biomarker for MCI as well as dementia in this population.
Assuntos
Disfunção Cognitiva/complicações , Disfunção Cognitiva/genética , Síndrome de Down/complicações , Síndrome de Down/genética , Encurtamento do Telômero/genética , Telômero/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Centrômero/metabolismo , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 21/genética , Feminino , Humanos , Interfase , Luz , Masculino , Metáfase , Pessoa de Meia-Idade , Ácidos Nucleicos Peptídicos/metabolismoRESUMO
We would like to submit the following correction to our recently published paper [...].