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Nature Reviews. Neurology Mar 2019Virtually all adults with Down syndrome (DS) show the neuropathological changes of Alzheimer disease (AD) by the age of 40 years. This association is partially due to... (Review)
Review
Virtually all adults with Down syndrome (DS) show the neuropathological changes of Alzheimer disease (AD) by the age of 40 years. This association is partially due to overexpression of amyloid precursor protein, encoded by APP, as a result of the location of this gene on chromosome 21. Amyloid-β accumulates in the brain across the lifespan of people with DS, which provides a unique opportunity to understand the temporal progression of AD and the epigenetic factors that contribute to the age of dementia onset. This age dependency in the development of AD in DS can inform research into the presentation of AD in the general population, in whom a longitudinal perspective of the disease is not often available. Comparison of the risk profiles, biomarker profiles and genetic profiles of adults with DS with those of individuals with AD in the general population can help to determine common and distinct pathways as well as mechanisms underlying increased risk of dementia. This Review evaluates the similarities and differences between the pathological cascades and genetics underpinning DS and AD with the aim of providing a platform for common exploration of these disorders.
Topics: Alzheimer Disease; Down Syndrome; Humans
PubMed: 30733618
DOI: 10.1038/s41582-018-0132-6 -
Journal of Neurodevelopmental Disorders Jun 2022Down syndrome regression disorder is a symptom cluster consisting of neuropsychiatric regression without cause. This study evaluated the incidence of neurodiagnostic...
BACKGROUND
Down syndrome regression disorder is a symptom cluster consisting of neuropsychiatric regression without cause. This study evaluated the incidence of neurodiagnostic abnormalities in individuals with Down syndrome regression disorder and determined if abnormalities are indicative of responses to therapeutic intervention.
METHODS
A retrospective, multi-center, case-control study was performed. Patients were required to have subacute onset and the presence of four of five symptom groups present (cognitive decline, expressive language, sleep derangement, loss of ability to perform activities of daily living, and/or a new movement disorder) and no other explanation for symptoms.
RESULTS
Individuals with Down syndrome regression disorder were comparable to a cohort of individuals with only Down syndrome although had higher rates of autoimmune disease (p = 0.02, 95%CI 1.04-1.75). Neurodiagnostic abnormalities were found on EEG (n = 19, 26%), neuroimaging (n = 16, 22%), and CSF (n = 9, 17%). Pleocytosis was appreciated in five cases, elevated total protein in nine, elevated IgG index in seven, and oligoclonal bands in two. Testing within 2 years of symptom onset was more likely to have neurodiagnostic abnormalities (p = 0.01, 95%CI 1.64-37.06). In individuals with neurodiagnostic abnormalities, immunotherapy was nearly four times more likely to have a therapeutic effect than in those without neurodiagnostic abnormalities (OR 4.11, 95%CI 1.88-9.02). In those with normal neurodiagnostic studies (n = 43), IVIg was effective in 14 of 17 (82%) patients as well although other immunotherapies were uniformly ineffective.
CONCLUSIONS
This study reports the novel presence of neurodiagnostic testing abnormalities in individuals with Down syndrome regression disorder, providing credence to this symptom cluster potentially being of neurologic and/or neuroimmunologic etiology.
Topics: Activities of Daily Living; Case-Control Studies; Down Syndrome; Humans; Immunotherapy; Neuroinflammatory Diseases; Retrospective Studies
PubMed: 35659536
DOI: 10.1186/s11689-022-09446-w -
Biochimica Et Biophysica Acta May 2016Down syndrome (DS) is a common cause of intellectual disability and is also associated with early age of onset of Alzheimer's disease (AD). Due to an extra copy of... (Review)
Review
Down syndrome (DS) is a common cause of intellectual disability and is also associated with early age of onset of Alzheimer's disease (AD). Due to an extra copy of chromosome 21, most adults over 40years old with DS have beta-amyloid plaques as a result of overexpression of the amyloid precursor protein. Cerebrovascular pathology may also be a significant contributor to neuropathology observed in the brains of adults with DS. This review describes the features of cardiovascular dysfunction and cerebrovascular pathology in DS that may be modifiable risk factors and thus targets for interventions. We will describe cerebrovascular pathology, the role of co-morbidities, imaging studies indicating vascular pathology and the possible consequences. It is clear that our understanding of aging and AD in people with DS will benefit from further studies to determine the role that cerebrovascular dysfunction contributes to cognitive health. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.
Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebrovascular Disorders; Down Syndrome; Humans
PubMed: 26593849
DOI: 10.1016/j.bbadis.2015.11.007 -
Developmental Neurobiology Jul 2019Down syndrome (DS) results in an overproduction of amyloid-β (Aβ) peptide associated with early onset of Alzheimer's disease (AD). DS cases have Aβ deposits... (Review)
Review
Down syndrome (DS) results in an overproduction of amyloid-β (Aβ) peptide associated with early onset of Alzheimer's disease (AD). DS cases have Aβ deposits detectable histologically as young as 12-30 years of age, primarily in the form of diffuse plaques, the type of early amyloid pathology also seen at pre-clinical (i.e., pathological aging) and prodromal stages of sporadic late onset AD. In DS subjects aged >40 years, levels of cortical Aβ deposition are similar to those observed in late onset AD and in addition to diffuse plaques involve cored plaques associated with dystrophic neurites (neuritic plaques), which are of neuropathological diagnostic significance in AD. The purpose of this review is to summarize and discuss findings from amyloid PET imaging studies of DS in reference to postmortem amyloid-based neuropathology. PET neuroimaging applied to subjects with DS has the potential to (a) track the natural progression of brain pathology, including the earliest stages of amyloid accumulation, and (b) determine whether amyloid PET biomarkers predict the onset of dementia. In addition, the question that is still incompletely understood and relevant to both applications is the ability of amyloid PET to detect Aβ deposits in their earliest form.
Topics: Amyloid beta-Peptides; Animals; Brain; Down Syndrome; Humans; Positron-Emission Tomography
PubMed: 31379087
DOI: 10.1002/dneu.22713 -
European Respiratory Review : An... Jun 2022Children with Down syndrome are at increased risk of sleep disordered breathing (SDB). SDB is associated with significant morbidity including neurocognitive impairment,... (Meta-Analysis)
Meta-Analysis Review
Children with Down syndrome are at increased risk of sleep disordered breathing (SDB). SDB is associated with significant morbidity including neurocognitive impairment, cardiometabolic disease and systemic inflammation. The identification of clinical markers that may predict SDB is critical in facilitating early diagnosis and treatment, and ultimately, preventing morbidity. The objective of this systematic review was to identify predictors of SDB in patients with Down syndrome. A search was conducted using MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Cumulative Index to Nursing and Allied Health Literature. A meta-analysis was performed according to the Meta-analyses of Observational Studies in Epidemiology checklist. Our review of the literature identified inconsistent associations between a variety of variables and SDB in children with Down syndrome, although the quality of evidence was poor. Meta-analysis of age and sex identified that children with OSA were older than those without OSA, and there was a similar risk of OSA in males and females, although risk favoured males. Currently, the American Academy of Pediatrics guidelines recommend that children with Down syndrome undergo polysomnography by the age of 4 years. Our review supports the recommendation for routine screening of children with Down syndrome. However, results from our meta-analysis suggest a need for longitudinal screening to diagnose children who may develop SDB as they get older.
Topics: Child; Child, Preschool; Down Syndrome; Female; Humans; Male; Polysomnography; Sleep Apnea Syndromes; Sleep Apnea, Obstructive
PubMed: 35768130
DOI: 10.1183/16000617.0026-2022 -
International Journal of Environmental... Jan 2021The objective of this study is to assess the evidence about the demographic transformation of the Down Syndrome population, with a specific focus on prenatal testing,...
The objective of this study is to assess the evidence about the demographic transformation of the Down Syndrome population, with a specific focus on prenatal testing, and to identify sources frequently used for demographic assessment of Down Syndrome in the world. We reviewed existing studies on demographic transformations in the population with Down Syndrome, specifically birthrate indicators, under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. The searches were made in Medline (via EBSCO Host), Academic Search Complete (via EBSCO Host), PsycINFO (via EBSCO Host), Web of Science (Core Collection), Public Health Database (via ProQuest), and The Cochrane Library. The terms were developed through Medical Subject Headings (MESH) and American Psycological Asociation Thesaurus of Psychological Index Terms (APA). Full texts were reviewed if information was given regarding location and birthrate for a range of three years or more, and if the first and last year considered was within 1960 and 2019. We found 22 references with a period of study between 1960 and 2019 following the global spread of prenatal testing for Down Syndrome. We found a consistent association between prenatal diagnosis and birthrate, enough to explain the significant fall in the prevalence of Down Syndrome, a somewhat rising incidence of Down Syndrome related to increased maternal age and extension of fertility services in healthcare systems, a generalized use of specific congenital birth defect registries as the primary source of data, and an unclear influence of socio-cultural and territorial variables. Our findings can inform research, policy, and practice to improve the reproductive health and quality of life of the population with Down Syndrome.
Topics: Birth Rate; Demography; Down Syndrome; Female; Humans; Maternal Age; Pregnancy; Prenatal Diagnosis; Quality of Life; United States
PubMed: 33466470
DOI: 10.3390/ijerph18010352 -
Genetics in Medicine : Official Journal... Apr 2020An entity of regression in Down syndrome (DS) exists that affects adolescents and young adults and differs from autism spectrum disorder and Alzheimer disease.
PURPOSE
An entity of regression in Down syndrome (DS) exists that affects adolescents and young adults and differs from autism spectrum disorder and Alzheimer disease.
METHODS
Since 2017, an international consortium of DS clinics assembled a database of patients with unexplained regression and age- and sex-matched controls. Standardized data on clinical symptoms and tiered medical evaluations were collected. Elements of the proposed definition of unexplained regression in DS were analyzed by paired comparisons between regression cases and matched controls.
RESULTS
We identified 35 patients with DS and unexplained regression, with a mean age at regression of 17.5 years. Diagnostic features differed substantially between regression cases and matched controls (p < 0.001 for all but externalizing behaviors). Patients with regression had four times as many mental health concerns (p < 0.001), six times as many stressors (p < 0.001), and seven times as many depressive symptoms (p < 0.001). Tiered medical evaluation most often identified abnormalities in vitamin D 25-OH levels, polysomnograms, thyroid peroxidase antibodies, and celiac screens. Analysis of the subset of patients with nondiagnostic medical evaluations reinforced the proposed definition.
CONCLUSIONS
Our case-control evidence supports a proposed definition of unexplained regression in Down syndrome. Establishing this clinical definition supports future research and investigation of an underlying mechanism.
Topics: Adolescent; Autism Spectrum Disorder; Case-Control Studies; Databases, Factual; Down Syndrome; Humans; Young Adult
PubMed: 31767984
DOI: 10.1038/s41436-019-0706-8 -
JNMA; Journal of the Nepal Medical... Dec 2022Down syndrome is a genetic disorder caused by an extra copy of chromosome number 21. New onset of seizure in adults with Down syndrome is rare. The exact pathogenesis of...
UNLABELLED
Down syndrome is a genetic disorder caused by an extra copy of chromosome number 21. New onset of seizure in adults with Down syndrome is rare. The exact pathogenesis of intracranial calcification and seizure in Down syndrome is unknown, however, a possible association between hypocalcemia and vitamin D deficiency in Down syndrome was reported. An 18-year-old girl with nasal bridge, mongoloid slants, clinodactyly and saddle gap of toes, and prominent Downs phenotypes was present with a low level of parathyroid hormone, calcium, and vitamin D. Due to a higher prevalence of intracranial calcification in people with Down syndrome, there is an increased possibility of hypocalcemia and vitamin D deficiency. Hence, serum levels of calcium and vitamin D should always be checked before starting treatment with anti-epileptic drugs.
KEYWORDS
basal ganglia; Down syndrome; seizure; trisomy 21.
Topics: Humans; Calcinosis; Calcium; Down Syndrome; Hypocalcemia; Hypoparathyroidism; Seizures; Vitamin D; Vitamin D Deficiency; Female; Adolescent
PubMed: 36705097
DOI: 10.31729/jnma.7950 -
Alzheimer's & Dementia : the Journal of... Jun 2015In 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)...
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.
Topics: Alzheimer Disease; Animals; Clinical Trials as Topic; Congresses as Topic; Disease Models, Animal; Down Syndrome; Drug Discovery; Humans; Neuropsychological Tests
PubMed: 25510383
DOI: 10.1016/j.jalz.2014.10.007 -
Aging Cell Jun 2019Down syndrome (DS) has been proposed by George Martin as a segmental progeroid syndrome since 1978. In fact, DS persons suffer from several age-associated disorders much... (Review)
Review
Down syndrome (DS) has been proposed by George Martin as a segmental progeroid syndrome since 1978. In fact, DS persons suffer from several age-associated disorders much earlier than euploid persons. Furthermore, a series of recent studies have found that DS persons display elevated levels of age biomarkers, thus supporting the notion that DS is a progeroid trait. Nowadays, due to the progressive advancements in social inclusion processes and medical assistance, DS persons live much longer than in the past; therefore, the early-onset health problems of these persons are becoming an urgent and largely unmet social and medical burden. In particular, the most important ailment of DS persons is the accelerated cognitive decline that starts when they reach about 40 years of age. This decline can be at least in part counteracted by multi-systemic approaches including early-onset cognitive training, physical activity, and psychosocial assistance. However, no pharmacological treatment is approved to counteract this decline. According to the most advanced conceptualization of Geroscience, tackling the molecular mechanisms underpinning the aging process should be a smart/feasible strategy to combat and/or delay the great majority of age-related diseases, including cognitive decline. We think that a debate is needed urgently on if (and how) this strategy could be integrated in protocols to face DS-associated dementia and overall unhealthy aging. In particular we propose that, on the basis of data obtained in different clinical settings, metformin is a promising candidate that could be exploited to counteract cognitive decline in DS.
Topics: Animals; Cognitive Aging; Down Syndrome; Humans
PubMed: 30768754
DOI: 10.1111/acel.12903