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Neurological phenotypes for Down syndrome across the life span
Open accessAbstract
This chapter reviews the neurological phenotype of Down syndrome (DS) in early development, childhood, and aging. Neuroanatomic abnormalities in DS are manifested as aberrations in gross brain structure as well as characteristic microdysgenetic changes. As the result of these morphological abnormalities, brain circuitry is impaired. While an intellectual disability is ubiquitous in DS, there is a wide range of variation in cognitive performance and a growing understanding between aberrant brain circuitry and the cognitive phenotype. Hypotonia is most marked at birth, affecting gait and ligamentous laxity. Seizures are bimodal in presentation with infantile spasms common in infancy and generalized seizures associated with cognitive decline observed in later years. While all individuals have the characteristic neuropathology of Alzheimer's disease (AD) by age 40 years, the prevalence of dementia is not universal. The tendency to develop AD is related, in part, to several genes on chromosome 21 that are overexpressed in DS. Intraneuronal accumulation of β-amyloid appears to trigger a cascade of neurodegeneration resulting in the neuropathological and clinical manifestations of dementia. Functional brain imaging has elucidated the temporal sequence of amyloid deposition and glucose metabolic rate in the development of dementia in DS. Mitochondrial abnormalities contribute to oxidative stress which is part of AD pathogenesis in DS as well as AD in the general population. A variety of medical comorbidities threaten cognitive performance including sleep apnea, abnormalities in thyroid metabolism, and behavioral disturbances. Mouse models for DS are providing a platform for the formulation of clinical trials with intervention targeted to synaptic plasticity, brain biochemistry, and morphological brain alterations.
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“One striking characteristic of people with DS is that at approximately 40–50 years of age, AD-like dementia often appears59,60.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [59]
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“It is likely that both a dose effect of triplication of APP and gene-environment interactions play a role59,60.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [59]
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“The varied phenotypes of DS result from full or partial triplication of chromosome 21, the most common human chromosomal disorder59.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [59]
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“Other proteins encoded on chromosome 21 may be involved59, such as Cu/Zn-superoxide dismutase (which is an important antioxidant enzyme normally, but can be deleterious if excess is present8) and Bach1 (transcriptional inhibitor of heme oxygenase-1, HO-1).”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [59]
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1 retracted
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RetractedCerebellum and nonmotor function
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“Beyond its effect on motor functioning, disorganized cerebellar output may impair higher order functioning such as emotion and cognition (Schmahmann, 2004; Teipel et al., 2004).”
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“…brain studies in autism have shown dysgenetic abnormalities in the frontal lobes, amygdala, and cerebellum—all areas that have been described as dysgenetic in DS. Recent reviews have suggested that the time course of brain development may be an important determining factor (Amaral et al., 2008).”
BackgroundOccurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome
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“The characteristic neuropathology of AD is present in the brains of individuals with DS by age 40 years (Mann and Esiri, 1989; Wisniewski et al., 1985).”
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BackgroundAmyloid A4 Protein and Its Precursor in Down's Syndrome and Alzheimer's Disease
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“In evaluation of the genes within the targeted chromosomal segment in Ts65Dn mice, it became apparent that an extra copy of the gene for APP contributed to decreased transport of nerve growth factor (Salehi et al., 2006).”
BackgroundCognitive deficits and associated neurological complications in individuals with Down's syndrome
Lott, I. T., & Dierssen, M. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70112-5 · Cited by 484 · cited 2×
“As recently reviewed (Lott and Dierssen, 2010), the cerebellum may be implicated in both cognition and affect in individuals with DS.”
BackgroundSelf-citation
Cited by
Sorted by citations
Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease
Butterfield, D. A., & Halliwell, B. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0132-6 · Cited by 1,954
The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates
Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., Monti, D., Capri, M., & Salvioli, S. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2018.00061 · Cited by 945
“At the age of 50, typical neuropathological hallmarks of AD appear in DS persons, including deposition of senile plaques containing amyloid β-peptide (Aβ), neurofibrillary tangles composed of hyperphosphorylated tau-P, and cholinergic and serotoninergic reduction (210).”
BackgroundDown syndrome: Cognitive and behavioral functioning across the lifespan
Grieco, J., Pulsifer, M., Seligsohn, K., Skotko, B., & Schwartz, A. (2015) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31439 · Cited by 377
Emerging connections between cerebellar development, behaviour and complex brain disorders
Sathyanesan, A., Zhou, J., Scafidi, J., Heck, D. H., Sillitoe, R. V., & Gallo, V. (2019) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0152-2 · Cited by 341
Down syndrome and the complexity of genome dosage imbalance
Antonarakis, S. E. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.154 · Cited by 314
Down syndrome and Alzheimer's disease: common pathways, common goals
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“Also, linking cognitive studies and functional imaging may allow prediction of cognitive impairment and provide a platform for early intervention [66].”
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Cellular Senescence in Neurodegenerative Diseases
Martínez‐Cué, C., & Rueda, N. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00016 · Cited by 299
“These cognitive alterations are due to defects in growth and differentiation of the CNS that appear during early prenatal stages (Haydar and Reeves, 2012; Lott, 2012).”
BackgroundDown syndrome: the brain in trisomic mode
Dierssen, M. (2012) · Nature reviews. Neuroscience · doi:10.1038/nrn3314 · Cited by 288
Atypical aging in down syndrome
Zigman, W. B. (2013) · Developmental Disabilities Research Reviews · doi:10.1002/ddrr.1128 · Cited by 262
Olmos-Serrano, J. L., Kang, H. J., Tyler, W. A., Silbereis, J. C., Cheng, F., Zhu, Y., Pletikos, M., Jankovic-Rapan, L., Cramer, N. P., Galdzicki, Z., et al. (2016) · Neuron · doi:10.1016/j.neuron.2016.01.042 · Cited by 239
“…analyses, because both regions have been implicated in DS neuropathology (Hartley et al., 2015; Haydar and Reeves, 2012; Letourneau et al., 2014; Lott, 2012) and exhibit diverse transcriptional profiles over the course 2 Neuron 89, 1–15, March 16, 2016 ª2016 Elsevier Inc. of development (Kang…”
Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis
Wilcock, D. M., & Griffin, W. S. T. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-84 · Cited by 230
“This patient, although of extremely advanced age for a person with DS, especially without the characteristic changes of AD [70], showed no clinical signs of dementia, and magnetic resonance imaging (MRI) 6 months before her death showed only minimal cerebral atrophy and no temporal lobe atrophy.”
BackgroundValenti, D., Lidia de, B. A. R. I., Filippis, B. D., Henrion‐Caude, A., & Vacca, R. A. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.01.012 · Cited by 203
Human Models Are Needed for Studying Human Neurodevelopmental Disorders
Zhao, X., & Bhattacharyya, A. (2018) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2018.10.009 · Cited by 192
Valenti, D., Rasmo, D. D., Signorile, A., Rossi, L., Lidia de, B. A. R. I., Scala, I., Granese, B., Papa, S., & Vacca, R. A. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.12.011 · Cited by 146
“Individuals with DS show an early aging associated with a decline in intellectual abilities, with a high tendency to develop neuropathological features associated with Alzheimer's disease [1,2].”
BackgroundNerve growth factor metabolic dysfunction in Alzheimer's disease and Down syndrome
Iulita, M. F., & Cuello, A. C. (2014) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.04.010 · Cited by 141
Gauthier, S. A., Pérez‐González, R., Sharma, A., Huang, F.-K., Alldred, M. J., Pawlik, M., Kaur, G., Ginsberg, S. D., Neubert, T. A., & Levy, E. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0466-0 · Cited by 125
The GABAergic Hypothesis for Cognitive Disabilities in Down Syndrome
Contestabile, A., Magara, S., & Cancedda, L. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00054 · Cited by 141
“DS patients and Ts65Dn mice demonstrate increased incidence of epileptic seizures (Stafstrom et al., 1991; Westmark et al., 2010; Rissman and Mobley, 2011; Lott, 2012; Robertson et al., 2015).”
BackgroundAziz, N. M., Guedj, F., Pennings, J. L. A., Olmos-Serrano, J. L., Siegel, A., Haydar, T. F., & Bianchi, D. W. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.031013 · Cited by 118
“…to identify suitable models for basic and translational studies (Bahado-Singh et al., 1992; Cardoso et al., 2015; Guidi et al., 2008; Haim et al., 2009; Larsen et al., 2008; Lott, 2012; Nilholm, 1999; Vicari et al., 2013; Winter et al., 1998; Wisniewski and Kida, 1994; Wisniewski et al., 1984).”
BackgroundButterfield, D. A., Domenico, F. D., Swomley, A. M., Head, E., & Marzia Perluigi, A. (2014) · Biochemical Journal · doi:10.1042/bj20140772 · Cited by 112
Gardiner, K. (2014) · Drug Design Development and Therapy · doi:10.2147/dddt.s51476 · Cited by 119
“Antioxidants Oxidative stress and mitochondrial dysfunction are both considered hallmarks of DS tissues and contributors to neurological phenotypes across the DS lifespan.(1,91) Cortical neurons derived from DS fetal brains show elevated levels of reactive oxygen species, and survival is enhanced by treatment with ant…”
InfluentialNeurologic complications of Down syndrome: a systematic review
Santoro, J. D., Pagarkar, D., Chu, D. T., Rosso, M., Paulsen, K. C., Levitt, P. R., & Rafii, M. S. (2020) · Journal of Neurology · doi:10.1007/s00415-020-10179-w · Cited by 119
Iulita, M. F., Ower, A., Barone, C., Pentz, R., Gubert, P., Romano, C., Cantarella, R. A., Elia, F., Buono, S., Recupero, M., et al. (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.05.001 · Cited by 99
“All r moderate-to-severe intellectual disability from early life and cognitive decline with advancing age [1,2].”
BackgroundKumar, S., Wirths, O., Theil, S., Gerth, J., Bayer, T. A., & Walter, J. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1107-8 · Cited by 101
García-Cerro, S., Rueda, N., Vidal, V., Lantigua, S., & Martínez-Cué, C. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.06.010 · Cited by 100
“Down syndrome (DS) is the most common genetic cause of intellectual disability (Shin et al., 2009) and is primarily caused by prenatal changes in central nervous system growth and differentiation (Lott, 2012; Haydar and Reeves, 2012).”
BackgroundDomenico, F. D., Pupo, G., Tramutola, A., Giorgi, A., Schininà, M. E., Coccia, R., Head, E., Butterfield, D. A., & Marzia Perluigi, A. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.03.027 · Cited by 98
“In addition to cognitive deficits, individuals with DS show signs of premature aging, immune disorders, and other clinical pathologies [6].”
BackgroundRETRACTED AND REPLACED: Nerve growth factor metabolic dysfunction in Down’s syndrome brains
Iulita, M. F., Carmo, S. D., Ower, A. K., Fortress, A. M., Aguilar, L. F., Hanna, M., Wısnıewskı, T., Granholm, A., Buhusi, M. C., Busciglio, J. A., et al. (2014) · Brain · doi:10.1093/brain/awt372 · Cited by 94
“It is well established that individuals with Down’s syndrome are at increased risk of developing premature ageing and Alzheimer’s disease dementia (Lott, 2012).”
RetractedFrontal white matter integrity in adults with Down syndrome with and without dementia
Powell, D. K., Caban‐Holt, A., Jicha, G. A., Robertson, W. C., Davis, R., Gold, B. T., Schmitt, F. A., & Head, E. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.01.137 · Cited by 90
“The most common cause of Down syndrome (DS) is triplication of chromosome 21, resulting in a phenotype that is accompanied by altered brain development and other neurologic features (Lott, 2012).”
Age-Related Changes of Adaptive and Neuropsychological Features in Persons with Down Syndrome
Ghezzo, A., Salvioli, S., Solimando, M. C., Palmieri, A., Chiostergi, C., Scurti, M., Lomartire, L., Bedetti, F., Cocchi, G., Follo, D., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113111 · Cited by 86
Franceschi, C., Garagnani, P., Gensous, N., Bacalini, M. G., Conte, M., & Salvioli, S. (2019) · Aging Cell · doi:10.1111/acel.12903 · Cited by 82
“able of taking into account the clinical heterogeneity of DS persons, particularly when they grow old (Lott, 2012).”
BackgroundInfluentialDi Domenico, F., Pupo, G., Mancuso, C., Barone, E., Paolini, F., Arena, A., Blarzino, C., Schmitt, F. A., Head, E., Butterfield, D. A., et al. (2015) · Journal of Alzheimer’s Disease · doi:10.3233/jad-141254 · Cited by 75
“Oxidative damage is also an early event in DS and might contribute to the development of deleterious DS phenotypes, including abnormal brain development and AD [3] [4] [5] [6].”
Sarkis, R. A., Dickerson, B. C., Cole, A. J., & Chemali, Z. N. (2015) · Journal of Neuropsychiatry · doi:10.1176/appi.neuropsych.15060143 · Cited by 75
“Future analysis of this particular subpopulation of patients with dementia and seizures is of interest because of the high prevalence of AD pathology after age 40 years and new-onset epilepsy.(25) A subset of patients (13%) had the occurrence of their seizures either preceding or occurring within 1 year of their cogni…”
BackgroundBrain insulin resistance triggers early onset Alzheimer disease in Down syndrome
Tramutola, A., Lanzillotta, C., Di Domenico, F., Head, E., Butterfield, D. A., Perluigi, M., & Barone, E. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104772 · Cited by 73
“This aspect appears of interest due to the observation that DS brain morphology continue to diverge compared with typically developing individuals (Lott, 2012).”
Aging with Down Syndrome—Where Are We Now and Where Are We Going?
Alldred, M. J., Martini, A. C., Patterson, D., Hendrix, J. A., & Granholm, A. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10204687 · Cited by 72
Down Syndrome Cognitive Phenotypes Modeled in Mice Trisomic for All HSA 21 Homologues
Belichenko, P. V., Kleschevnikov, A. M., Becker, A., Wagner, G. E., Lysenko, L. V., Yu, Y. E., & Mobley, W. C. (2015) · PLoS ONE · doi:10.1371/journal.pone.0134861 · Cited by 73
“We conclude that the TTS mouse demonstrates a number of motor phenotypes that are similar to those in DS [100], but different from the corresponding phenotypes observed in other mouse DS models.”
ResultNew approaches to studying early brain development in Down syndrome
Baburamani, A. A., Patkee, P. A., Arichi, T., & Rutherford, M. A. (2019) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.14260 · Cited by 74
“Other techniques, such as the neurite orientation distribution and density imaging model can also provide measures of the neurite density index and orientation dispersion index which may help explore the cortical synaptic and dendritic developmental abnormalities that are widely reported in Down syndrome.(9,41) Althou…”
BackgroundMethodSynaptophysin and Synaptojanin-1 in Down Syndrome are Differentially Affected by Alzheimer's Disease
Martin, S. B., Dowling, A. L. S., Lianekhammy, J., Lott, I. T., Doran, E., Murphy, M. P., Beckett, T. L., Schmitt, F. A., & Head, E. (2014) · Journal of Alzheimer's Disease · doi:10.3233/jad-140795 · Cited by 64
“The gene for SYNJ1 is on chromosome 21 and present in triplicate in DS [21].”
Self-citationTyrer, F., Dunkley, A. J., Singh, J., Kristunas, C., Khunti, K., Bhaumik, S., Davies, M. J., Yates, T. E., & Gray, L. J. (2018) · Journal of Intellectual Disability Research · doi:10.1111/jir.12571 · Cited by 67
Neuroimaging assessment in Down syndrome: a pictorial review
Rodrigues, M., Nunes, J., Figueiredo, S., de Campos, A. M., & Geraldo, A. F. (2019) · Insights into Imaging · doi:10.1186/s13244-019-0729-3 · Cited by 60
Kaur, G., Sharma, A., Xu, W., Gerum, S., Alldred, M. J., Subbanna, S., Basavarajappa, B. S., Pawlik, M., Ohno, M., Ginsberg, S. D., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.5338-13.2014 · Cited by 58
“To date, the mechanism(s) underlying these intellectual disabilities and age-related cognitive decline in DS is unclear, although data suggest that a wide array of neurochemical changes may compromise cognitive performance in DS (Cataldo et al., 2000; Lott, 2012).”
BackgroundImpact of increased APP gene dose in Down syndrome and the Dp16 mouse model
Sawa, M., Overk, C., Becker, A., Derse, D., Albay, R., Weldy, K., Salehi, A., Beach, T. G., Doran, E., Head, E., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12463 · Cited by 54
Disturbance of redox homeostasis in Down Syndrome: Role of iron dysmetabolism
Barone, E., Arena, A., Head, E., Butterfield, D. A., & Marzia Perluigi, A. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.07.009 · Cited by 55
“DS individuals, after the age of 40, develop a type of dementia that is similar to AD, the most common cause of dementia in the elderly population, with deposition of senile plaques containing amyloid beta-peptide (Aβ), neurofibrillary tangles (NFTs) composed of hyperphoshorylated tau, and cholinergic and serotonergic…”
BackgroundRole of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer's Disease
Potter, H., Granic, A., & Caneus, J. (2015) · Current Alzheimer Research · doi:10.2174/156720501301151207100616 · Cited by 54
“This finding provided the first direct evidence that three copies of the APP gene alone are sufficient to yield earlyonset, fully penetrant familial AD, although it is noteworthy that some people with trisomy 21 DS appear to be protected from developing AD dementia, despite having AD neuropathology [3].”
Sensory Processing and Maladaptive Behavior: Profiles Within the Down Syndrome Phenotype
Will, E., Daunhauer, L. A., Fidler, D. J., Lee, N., Rosenberg, C. R., & Hepburn, S. (2019) · Physical & Occupational Therapy In Pediatrics · doi:10.1080/01942638.2019.1575320 · Cited by 53
“Hypotonia (i.e., low muscle tone; for a review see Lott, 2012), for example, is characteristic to DS and speculated to affect attainment of motor milestones and other areas of development (Fidler et al., 2011).”
BackgroundPonroy Bally, B., Farmer, W. T., Jones, E. V., Jessa, S., Kacerovsky, J. B., Mayran, A., Peng, H., Lefebvre, J. L., Drouin, J., Hayer, A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa003 · Cited by 49
Lanzillotta, C., Tramutola, A., Di Giacomo, G., Marini, F., Butterfield, D. A., Di Domenico, F., Perluigi, M., & Barone, E. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.01.042 · Cited by 47
The rise and fall of insulin signaling in Alzheimer’s disease
Chami, B., Steel, A. J., de la Monte, S. M., & Sutherland, G. T. (2016) · Metabolic Brain Disease · doi:10.1007/s11011-016-9806-1 · Cited by 48
Kleschevnikov, A. M., Yu, J., Kim, J., Lysenko, L. V., Zeng, Z., Yu, Y. E., & Mobley, W. C. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.03.009 · Cited by 49
“…are cognitive and behavioral impairments in children and the emergence of Alzheimer’s disease in the elderly (Belichenko et al., 2016; Dierssen, 2012; Dykens, 2007; Kleschevnikov et al., 2012c; Lott, 2012; Nadel, 2003; Roizen and Patterson, 2003; Roper and Reeves, 2006; Sabbagh and Edgin, 2016).”
BackgroundIGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome
Araya, P., Kinning, K. T., Coughlan, C., Smith, K. P., Granrath, R. E., Enriquez-Estrada, B. A., Worek, K., Sullivan, K. D., Rachubinski, A. L., Wolter-Warmerdam, K., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111883 · Cited by 50
GIRK Channels Mediate the Nonphotic Effects of Exogenous Melatonin
Hablitz, L. M., Molzof, H. E., Abrahamsson, K. E., Cooper, J. M., Prosser, R. A., & Gamble, K. L. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.1597-15.2015 · Cited by 44
Stem and progenitor cell dysfunction in human trisomies
Liu, B., Filippi, S., Roy, A., & Roberts, I. A. G. (2014) · EMBO Reports · doi:10.15252/embr.201439583 · Cited by 44
“2007 [199]; Lott 2012 [18]; Lockrow et al.”
InfluentialBlock, A., Ahmed, M. M., Dhanasekaran, A. R., Tong, S., & Gardiner, K. J. (2015) · Biology of Sex Differences · doi:10.1186/s13293-015-0043-9 · Cited by 43
“Of particular importance, now that the life span of people with DS has increased to >60 years, is the universal development of the pathology of AD by age 30 and the development in half of those with DS of an AD-like dementia by the age of 50 [27].”
BackgroundLanguage Development in Individuals With Intellectual and Developmental Disabilities
(2016) · International Review of Research in Developmental Disabilities · doi:10.1016/bs.irrdd.2016.05.006 · Cited by 43
Estimates of the prevalence of speech and motor speech disorders in adolescents with Down syndrome
Wilson, E. M., Abbeduto, L., Camarata, S., & Shriberg, L. D. (2019) · Clinical Linguistics & Phonetics · doi:10.1080/02699206.2019.1595735 · Cited by 42
“The presence of generalized hypotonia in individuals with DS is well-documented in the literature (Lott, 2012) and reportedly plays a role in delayed motor skill acquisition; however, a conclusive causal association between hypotonia and delayed motor development in children with DS has not been…”
Marzia Perluigi, A., Tramutola, A., Pagnotta, S. E., Barone, E., & Butterfield, D. A. (2020) · Antioxidants · doi:10.3390/antiox9090779 · Cited by 44
Modeling Neurodevelopmental Disorders Using Human Pluripotent Stem Cells
Telias, M., & Ben‐Yosef, D. (2014) · Stem Cell Reviews and Reports · doi:10.1007/s12015-014-9507-2 · Cited by 43
“Down syndrome (DS) is the most common form of intellectual disability, with the affected individuals having an average IQ of 50 [160–163].”
Dissecting Alzheimer disease in Down syndrome using mouse models
Choong, X. Y., Tosh, J., Pulford, L. J., & Fisher, E. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00268 · Cited by 41
“…although this can be difficult to determine, particularly as DS has been characterized as a syndrome of accelerated aging in both clinical (Lott, 2012; Zigman, 2013) and epigenetic terms (Horvath et al., 2015), and because aging remains the clearest non-genetic risk factor for all forms…”
Backgroundvan den Bemd, M., Schalk, B. W. M., Bischoff, E. W. M. A., Cuypers, M., & Leusink, G. L. (2022) · Family Practice · doi:10.1093/fampra/cmac042 · Cited by 44
Alzheimer's Disease Modeling: Ups, Downs, and Perspectives for Human Induced Pluripotent Stem Cells
Wojda, U., & Kuźnicki, J. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-121984 · Cited by 40
Alldred, M. J., Chao, H. M., Lee, S. H., Beilin, J., Powers, B. E., Petkova, E., Strupp, B. J., & Ginsberg, S. D. (2018) · Hippocampus · doi:10.1002/hipo.22832 · Cited by 35
“DS is also the primary genetic cause of intellectual disability (ID), with cognitive deficits in hippocampal-dependent learning and memory, attention, and language and communication skills (Chapman & Hesketh, 2000; Esbensen, 2010; Lott, 2012; Rachidi & Lopes, 2008, 2010).”
BackgroundThe Fragile X proteins Fmrp and Fxr2p cooperate to regulate glucose metabolism in mice
Lumaban, J. G., & Nelson, D. L. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu737 · Cited by 37
Alldred, M. J., Lee, S. H., Stutzmann, G. E., & Ginsberg, S. D. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.707950 · Cited by 34
“…and basal forebrain cholinergic neuron (BFCN) degeneration, with the accompanying cognitive decline, typically by the mid-third decade of life (Mann et al., 1984; Coyle et al., 1988; Beacher et al., 2009; Lott and Dierssen, 2010; Costa, 2012; Lott, 2012; Hartley et al., 2015; Annus et al., 2016).”
BackgroundSoy Infant Formula and Seizures in Children with Autism: A Retrospective Study
Westmark, C. J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0080488 · Cited by 34
Netrin‐1 induces local translation of down syndrome cell adhesion molecule in axonal growth cones
Jain, S., & Welshhans, K. (2015) · Developmental Neurobiology · doi:10.1002/dneu.22360 · Cited by 33
“Nevertheless, our findings can be considered in the context of the Down syndrome human brain phenotype, which includes reduced neuronal connectivity (Wang et al., 1992; Teipel et al., 2003; Gotti et al., 2011; Lott, 2012).”
BackgroundDementia in intellectual disability
Sheehan, R., Ali, A., & Hassiotis, A. (2014) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000032 · Cited by 33
“The neuropathology underlying the association of Down syndrome with dementia is not clear, although triplication of genes on chromosome 21, including the amyloid precursor protein (APP) gene, has been implicated [8].”
BackgroundWu, C.-I., Vinton, E. A., Pearse, R. V., Heo, K., Aylward, A. J., Hsieh, Y., Bi, Y., Adeleye, S., Fancher, S. B., Duong, D. M., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01454-5 · Cited by 34
Deutsch, S. I., Burket, J. A., & Benson, A. D. (2014) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2014.05.011 · Cited by 34
Dashinimaev, E. B., Artyuhov, A., Bolshakov, A. P., Vorotelyak, E. A., & Vasiliev, A. V. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-160945 · Cited by 32
Obstructive sleep apnoea/hypopnoea syndrome in adults with Down syndrome
Hill, E. A. (2016) · Breathe · doi:10.1183/20734735.012116 · Cited by 32
“These deficits are related to structural and functional changes within the brain, some present from birth and others, such as plaques and tangles associated with dementia, acquired over time [5–7].”
Dumortier, L., & Bricout, V. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.10.018 · Cited by 33
Modeling epileptic spasms during infancy: Are we heading for the treatment yet?
Velı́šek, L., & Velı́šková, J. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107578 · Cited by 31
“Finally, the model does not provide age-specificity while in patients with trisomy 21, IS occur only during infancy and later different types of seizures prevail (Beatty, et al., 2017; Lott, 2012).”
MethodNew Perspectives for the Rescue of Cognitive Disability in Down Syndrome
Bartesaghi, R., Haydar, T. F., Delabar, J. M., Dierssen, M., Martínez‐Cué, C., & Bianchi, D. W. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.2775-15.2015 · Cited by 32
Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice
Rueda, N., Vidal, V., García-Cerro, S., Narcís, J. O., Llorens-Martı́n, M., Corrales, A., Lantigua, S., Iglesias, M., Merino, J., Merino, R., et al. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.05.008 · Cited by 31
“This intellectual disability is primarily caused by prenatal changes in central nervous system growth and differentiation (Lott, 2012; Haydar and Reeves, 2012).”
BackgroundAging With Down Syndrome: The Dual Diagnosis: Alzheimer’s Disease and Down Syndrome
Cipriani, G., Danti, S., Carlesi, C., & Fiorino, M. D. (2018) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317518761093 · Cited by 32
Cellular polyamines condense hyperphosphorylated Tau, triggering Alzheimer’s disease
Ivanov, S. M., Atanasova, M., Dimitrov, I., & Doytchinova, I. A. (2020) · Scientific Reports · doi:10.1038/s41598-020-67119-x · Cited by 29
Iulita, M. F., Caraci, F., & Cuello, A. C. (2016) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527315666160321104916 · Cited by 28
Incontinence in persons with Down Syndrome
Niemczyk, J., von Gontard, A., Equit, M., Medoff, D., Wagner, C., & Curfs, L. (2016) · Neurourology and Urodynamics · doi:10.1002/nau.23146 · Cited by 28
“In DS, neuroanatomic alterations (reduced brain weight, smaller volumes of hippocampus, temporal lobes, and cerebellum) and histological findings (decreased number of neurons, neuronal density, neuronal distribution, and synaptic density) support the hypothesis of an abnormal neuronal connectivity.(21) It can be hypot…”
Kazim, S. F., Blanchard, J., Bianchi, R., & Iqbal, K. (2017) · Scientific Reports · doi:10.1038/srep45561 · Cited by 28
“This process ultimately leads to recognition memory, which consists of two components: (1) familiarity, a global awareness of the features of a stimulus, and (2) recollection, knowledge of the stimulus in the context of other information, such as what, where, or under which context the stimulus was encountered115–118.”
BackgroundSoriano, L. D. H., Thurman, A. J., & Abbeduto, L. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00424 · Cited by 28
“Indeed, the cognitive and behavioral pattern described for DS in the current study might differ dramatically at a later age as a consequence of their high risk of developing the neuropathology associated wi9th Alzheimer’s Disease and the resulting dementia-like symptoms (Lott, 2012).”
BackgroundMartínez‐Cué, C., & Rueda, N. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186906 · Cited by 26
“The cognitive alterations found in DS are primarily caused by prenatal changes in central nervous system (CNS) growth and differentiation [3,4].”
BackgroundLondon, J., Rouch, C., Bui, L. C., Assayag, E., Souchet, B., Daubigney, F., Medjaoui, H., Luquet, S. H., Magnan, C., Delabar, J. M., et al. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0591-6 · Cited by 29
Measuring Health-Related Quality of Life of Adults With Down Syndrome
Graves, R., Graff, J. C., Esbensen, A. J., Hathaway, D., Wan, J. Y., & Wicks, M. N. (2016) · American Journal on Intellectual and Developmental Disabilities · doi:10.1352/1944-7558-121.4.312 · Cited by 26
Down syndrome: age-dependence of PiB binding in postmortem frontal cortex across the lifespan
LeVine, H., Spielmann, H. P., Matveev, S., Cauvi, F. M., Murphy, M. P., Beckett, T. L., McCarty, K. L., Lott, I. T., Doran, E. W., Schmitt, F. A., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.03.005 · Cited by 26
“Down syndrome (DS) or trisomy 21 is the most common genetic cause of intellectual disability and is associated with a neurologic phenotype that includes the development of AD neuropathology by the age of 40 years (Head et al., 2016; Lott, 2012; Lott and Dierssen, 2010).”
BackgroundSelf-citationCôté, V., Lalancette, È., Knoth, I. S., Côté, L., Agbogba, K., Vannasing, P., Major, P., Barlaam, F., Michaud, J. L., & Lippé, S. (2020) · Brain Research · doi:10.1016/j.brainres.2020.147205 · Cited by 25
Gholipour, T., Mitchell, S. B., Sarkis, R. A., & Chemali, Z. N. (2017) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2016.12.014 · Cited by 25
Treatment Considerations for Obstructive Sleep Apnea in Pediatric Down Syndrome
Gastelum, E., Cummins, M., Singh, A., Montoya, M. J., Urbano, G. L., & Tablizo, M. A. (2021) · Children · doi:10.3390/children8111074 · Cited by 24
“Generalized hypotonia is nearly universal in children with DS [11].”
BackgroundAge‐Related Cortical Thickness Reduction in Non‐Demented Down's Syndrome Subjects
Romano, A., Cornia, R., Moraschi, M., Bozzao, A., Chiacchiararelli, L., Coppola, V., Iani, C., Stella, G., Albertini, G., & Pierallini, A. (2015) · Journal of Neuroimaging · doi:10.1111/jon.12259 · Cited by 25
Challenges and Opportunities for Translation of Therapies to Improve Cognition in Down Syndrome
Lee, S. E., Duran-Martinez, M., Khantsis, S., Bianchi, D. W., & Guedj, F. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.10.001 · Cited by 25
“All individuals with DS exhibit significant hypoplasia of the frontal lobe, hippocampus, and cerebellum, and mild to severe intellectual disability [2, 3].”
BackgroundGenetic and Epigenetic Mechanisms in Down Syndrome Brain
Lu, J., & Shee, V. (2013) · InTech eBooks · doi:10.5772/52807 · Cited by 24
“Several HSA21 genes have been implicated in generation of ROS including DYRK1A, DSCR1, SOD1, ETS2, S100B, APP and BACH1 [15, 17].”
BackgroundDopaminergic Perturbation in the Aetiology of Neurodevelopmental Disorders
Ijomone, O. K., Oria, R. S., Ijomone, O. M., Aschner, M., & Bornhorst, J. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04418-8 · Cited by 22
“Such deficiencies are linked to neuroanatomical problems such as decreased brain weight and size, delayed lamination, and aberrant dendritic and spine formation [167, 168].”
Lysenko, L. V., Kim, J., Madamba, F., Tyrtyshnaia, A. A., Ruparelia, A., & Kleschevnikov, A. M. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.03.005 · Cited by 21
“Down syndrome (DS) is the most common genetic cause of intellectual disability in children and adults (Chapman and Hesketh, 2000; Dierssen, 2012; Gardiner et al., 2010; Lott, 2012; Roizen and Patterson, 2003; Wiseman et al., 2009).”
BackgroundGene Expression Studies in Down Syndrome: What Do They Tell Us about Disease Phenotypes?
Chapman, L., Ramnarine, I. V. P., Zemke, D., Majid, A., & Bell, S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052968 · Cited by 23
“These manifest as hypotonia at birth, abnormal gait, ligamentous laxity, seizures, intellectual disability and early neuropathological changes in Alzheimer’s disease (often by 40 years old) [49].”
BackgroundSoriano, L. D. H., Thurman, A. J., Harvey, D. J., Kover, S. T., & Abbeduto, L. (2020) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-020-09320-7 · Cited by 21
“For example, the observed changes with age aimed to vary with the nature of the disability might differ dramatically at a later age as a consequence of the high risk of developing the neuropathology associated with Alzheimer’s disease and the resulting dementia-like symptoms for those with DS [119].”
BackgroundAbukhaled, Y., Hatab, K., Awadhalla, M., & Hamdan, H. (2023) · Journal of Neurology · doi:10.1007/s00415-023-11890-0 · Cited by 30
“As for neurological system , it is important to consider 3 different categories: neurodevelopmental, psychotic, and neurological [12].”
BackgroundDay, S. M., Yang, W., Wang, X., Stern, J. E., Zhou, X., Macauley, S. L., & Ma, T. (2019) · eNeuro · doi:10.1523/eneuro.0031-19.2019 · Cited by 21
“Impaired cognition is a hallmark of DS, and there are currently no effective treatments that improve cognitive function in individuals with DS (Patterson, 2009; Lana-Elola et al., 2011; Lott, 2012).”
BackgroundMitsogiannis, M. D., Pancho, A., Aerts, T., Sachse, S., Vanlaer, R., Noterdaeme, L., Schmucker, D., & Seuntjens, E. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.624181 · Cited by 22
“Given the reduced cell number and anomalous neuronal organization observed within specific neocortex regions and layers of DS brains already at mid-to-late gestational stages (Colon, 1972; Becker et al., 1991; Golden and Hyman, 1994; Haydar and Reeves, 2012; Lott, 2012), we sought to examine the effects of Dscam and D…”
BackgroundInfluentialGiannasi, L. C., Politti, F., Dutra, M. T. D. S., Tenguan, V. L. S., Silva, G. R. C., de Mancilha, G. P., da Silva, D. B., de Oliveira, L. V. F., Oliveira, C. S., Amorim, J. B. O., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-63963-z · Cited by 20
Down Syndrome, Ageing and Epigenetics
Gensous, N., Franceschi, C., Salvioli, S., Garagnani, P., & Bacalini, M. G. (2019) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-981-13-3681-2_7 · Cited by 19
Searching for new pharmacological targets for the treatment of Alzheimer's disease in Down syndrome
Caraci, F., Iulita, M. F., Pentz, R., Flores Aguilar, L., Orciani, C., Barone, C., Romano, C., Drago, F., & Cuello, A. C. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.10.004 · Cited by 18
Hair Mineral and Trace Element Content in Children with Down’s Syndrome
Grabeklis, A. R., Skalny, A. V., Skalnaya, A. A., Zhegalova, I. V., Notova, S. V., Mazaletskaya, A. L., Геннадиевна, С. М., & Tinkov, A. A. (2018) · Biological Trace Element Research · doi:10.1007/s12011-018-1506-8 · Cited by 18
Metadata
- Authors
- Lott, I. T.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Lott, Ira T.
- ORCID
- Lott, Ira T.
- Venue
- Progress in Brain Research
- Publisher
- Elsevier
- Published
- 2012
- Volume
- 197
- Pages
- 101-121
- ISSN
- 0079-6123 (ISSN-L)
- PMC
- PMC3417824
- OpenAlex
- W1829879414
- Cited by
- 225
- References
- 163
- Citations by year
- 2026: 6 · 2025: 18 · 2024: 13 · 2023: 14 · 2022: 19 · 2021: 22 · 2020: 21 · 2019: 14 · 2018: 15 · 2017: 18 · 2016: 13 · 2015: 17 · 2014: 22 · 2013: 10 · 2012: 3
- FWCI
- 38.75
- Type
- book chapter
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Progress in brain research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG 21912, P50AG016573, R01AG021912)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD065160, HD 37427, HD-065160, R01HD037427)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Down syndrome, neurological phenotype, intellectual disability, brain circuits, hypotonia, infantile spasms, seizures, Alzheimer's disease, dementia, chromosome 21 genes, amyloid-beta, neurodegeneration, glucose metabolism, mitochondrial dysfunction, oxidative stress, sleep apnea, thyroid metabolism, behavioral problems, mouse model, synaptic plasticity, aging
- MeSH terms
- Age Factors, Aging, Brain, Cognition Disorders, Down Syndrome, Humans, Muscle Hypotonia, Nervous System Diseases, Phenotype, Amyloid beta-Peptides, Mitochondrial Diseases
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