Developmental deficits and staging of dynamics of age associated Alzheimer’s disease neurodegeneration and neuronal loss in subjects with Down syndrome (original) (raw)
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Aging in Down Syndrome and the Development of Alzheimer’s Disease Neuropathology
Chromosome 21, triplicated in Down Syndrome, contains several genes that are thought to play a critical role in the development of AD neuropathology. The overexpression of the gene for the amyloid precursor protein (APP), on chromosome 21, leads to early onset beta-amyloid (Aβ) plaques in DS. In addition to Aβ accumulation, middle-aged people with DS develop neurofibrillary tangles, cerebrovascular pathology, white matter pathology, oxidative damage, neuroinflammation and neuron loss. There is also evidence of potential compensatory responses in DS that benefit the brain and delay the onset of dementia after there is sufficient neuropathology for a diagnosis of AD. This review describes some of the existing literature and also highlights gaps in our knowledge regarding AD neuropathology in DS. It will be critical in the future to develop networked brain banks with standardized collection procedures to fully characterize the regional and temporal pathological events associated with aging in DS. As more information is acquired regarding AD evolution in DS, there will be opportunities to develop interventions that are age-appropriate to delay AD in DS.
A longitudinal study of brain anatomy changes preceding dementia in Down syndrome
NeuroImage: Clinical, 2018
Background: We longitudinally assessed Down syndrome individuals at the age of risk of developing dementia to measure changes in brain anatomy and their relationship to cognitive impairment progression. Methods: Forty-two Down syndrome individuals were initially included, of whom 27 (mean age 46.8 years) were evaluable on the basis of completing the 2-year follow-up and success in obtaining good quality MRI exams. Voxel-based morphometry was used to estimate regional brain volumes at baseline and follow-up on 3D anatomical images. Longitudinal volume changes for the group and their relationship with change in general cognitive status and specific cognitive domains were mapped. Results: As a group, significant volume reduction was identified in the substantia innominata region of the basal forebrain, hippocampus, lateral temporal cortex and left arcuate fasciculus. Volume reduction in the substantia innominata and hippocampus was more prominent in individuals whose clinical status changed from cognitively stable to mild cognitive impairment or dementia during the follow-up. Relevantly, longitudinal memory score change was specifically associated with volume change in the hippocampus, prospective memory with prefrontal lobe and verbal comprehension with language-related brain areas. Conclusions: Results are notably concordant with the well-established anatomical changes signaling the progression to dementia in Alzheimer's disease, despite the dense baseline pathology that developmentally accumulates in Down syndrome. This commonality supports the potential value of Down syndrome as a genetic model of Alzheimer's neurodegeneration and may serve to further support the view that Down syndrome patients are best candidates to benefit from treatment research in Alzheimer's disease.
Alzheimer's Disease in Down Syndrome
European journal of neurodegenerative disease, 2012
A key challenge to adults with Down syndrome (DS) as they age is an increased risk for cognitive decline, dementia, and Alzheimer disease (AD). In DS persons ranging from 40-49 years of age, 5.7-55% may be clinically demented and between 50-59 years, dementia prevalence ranges from 4-55% (reviewed in [1]). Despite the wide ranges reported for dementia prevalence, a consistent feature of aging in DS is the progressive accumulation of AD brain pathologies. By the age of 40 years, virtually all have sufficient senile plaques and neurofibrillary tangles for a neuropathological diagnosis of AD [2]. Thus, there is dissociation between the age of onset of AD neuropathology (40 years) and increasing signs of clinical dementia. We discuss the hypothesis that frontal impairments are a critical factor affecting cognitive function and are associated with white matter (WM) and AD neuropathology. While these may be an early sign of conversion to dementia, we also review several other clinical com...
Discrepancy between Alzheimer-Type Neuropathology and Dementia in Persons with Down's Syndrome
Annals of The New York Academy of Sciences, 1986
Alzheimer's disease (AD) is a progressive dementing disorder, with distinct neuropathology, that affects about 10% of people over 65 years of age. Down's syndrome (DS), a chromosomal abnormality, is a major known cause of mental retardation; the disorder occurs in one out of every thousand live births. I It is commonly thought that persons with DS succumb to AD not only at a much earlier age, but also in much larger numbers than people without DS. A critical examination of this view is the essence of this presentation.
Dementia in Down’s syndrome: an MRI comparison with Alzheimer’s disease in the general population
Journal of Neurodevelopmental Disorders, 2013
Background: Down's syndrome (DS) is the most common genetic cause of intellectual disability. People with DS are at an increased risk of Alzheimer's disease (AD) compared to the general population. Neuroimaging studies of AD have focused on medial temporal structures; however, to our knowledge, no in vivo case-control study exists comparing the anatomy of dementia in DS to people with AD in the general population. We therefore compared the in vivo brain anatomy of people with DS and dementia (DS+) to those with AD in the general population.
2022
Several recent epidemiological studies attempted to identify risk factors for Alzheimer's disease. Age, family history, genetic factors (APOE genotype, trisomy 21), physical activity, and a low level of schooling are significant risk factors. In this review, we summarize the known psychosocial risk factors for the development of Alzheimer's disease in patients with Down syndrome and their association with neuroanatomical changes in the brains of people with Down syndrome. We completed a comprehensive review of the literature on PubMed, Google Scholar, and Web of Science about psychosocial risk factors for Alzheimer's disease, for Alzheimer's disease in Down syndrome, and Alzheimer's disease in Down syndrome and their association with neuroanatomical changes in the brains of people with Down syndrome. Alzheimer's disease causes early pathological changes in individuals with Down syndrome, especially in the hippocampus and corpus
Several recent epidemiological studies attempted to identify risk factors for Alzheimer's disease. Age, family history, genetic factors (APOE genotype, Down syndrome), physical activity, and a low level of schooling are significant risk factors. In this review, we summarize the known psychosocial risk factors for the development of Alzheimer's disease in Down syndrome patients and their association with neuroanatomical changes in the brains of people with Down syndrome. We completed a comprehensive review of the literature on PubMed, Google Scholar, and Web of Science about psychosocial risk factors for Alzheimer's disease, for Alzheimer's disease in Down syndrome, and Alzheimer's disease in Down syndrome and their association with neuroanatomical changes in the brains of people with Down syndrome. Alzheimer's disease causes early pathological changes in Down syndrome patients, especially in the hippocampus and corpus callosum. The field needs more data about the neuroanatomical changes during childhood, how they change with increasing age, and the presence or absence of psychosocial risk factors. Further neuroimaging and psychosocial assessment-focused research is needed to understand the mechanisms leading to Alzheimer's disease at an early age and create more sensitive and relevant clinical, memory, and reasoning assessments for people with Down syndrome.
Early age-related progression of AD-like neuropathology in Down’s syndrome
American Journal of Neurodegenerative Disease, 2013
We have previously reported that increased numbers of Alz-50-reactive (apoptotic) neurons occurred in young DS subjects compared to controls, but increased in density with increasing age, and in advance of identifiable senile plaques (SP) in DS. The purpose of the study was to determine if there are further differences in Alzheimer’s disease (AD)-like neuropathology with increasing age among individuals with Down’s syndrome (DS) compared to cognitively normal age-matched controls. The two populations compared were age-matched normal controls (N = 14) between 11 months and 61 years of age and individuals with DS (N = 8) between 1 and 54 years of age. There were 7 cognitively intact DS and 10 control subjects under 35 years of age. The single demented 54 year old DS subject was compared to 4 non-demented controls between 48 and 61 years of age. 50 μm Vibratome sections of formalin fixed hippocampal formations were immunohistochemically stained for amyloid-β (6E10), APP (22C11) and phosphorylated tau (AT8) using standard methods. AT8 immunoreactive features were found only in the oldest DS subject. In contrast, the number and intensity of amyloid-β-immunoreactive neurons were maximal in the youngest DS subjects (1-24 years), reduced in the young adults (25-35 years) synchronous with the appearance of only diffuse-form SP, and were further reduced in the 54 year-old DS subject exhibiting abundant multiform SP. Distribution of APP immunoreactivity (22C11) was distinct from amyloid-β (6E10) in appearance and by location and age in both DS and normal controls. The data indicates that the earliest observable neuropathologic feature in DS may be neuronal accumulation of amyloid-β. Such accumulation of amyloid-β occurs decades in advance of deposition as SP, which in turn occurs decades before cognitive decline.
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2021
Introduction: Down syndrome (DS), a genetic variant of early onset Alzheimer's disease (AD), lacks a suitable outcome measure for prevention trials targeting predementia stages. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.