The DOI matches its Crossref record; 160 of the 163 references it cites were found in a registry or an index.
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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Citations
Cites
1 retracted
Andriolo, R. B., Dib, R. E., Ramos, L., Atallah, Á. N., & da Silva, E. M. (2009) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd005176.pub3 · Cited by 10
RetractedCerebellum and nonmotor function
Strick, P. L., Dum, R. P., & Fiez, J. A. (2009) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.31.060407.125606 · Cited by 1,777 · cited 1×
“It seems plausible that neuropsychological abnormalities in DS such as impaired attention, executive control, language learning, working memory, and emotional responses may reflect dysfunction in the cerebellar–cortical–limbic circuitry (Strick et al., 2009).”
BackgroundSchmahmann, J. D. (2004) · Journal of Neuropsychiatry · doi:10.1176/jnp.16.3.367 · Cited by 1,493 · cited 1×
“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).”
BackgroundAmaral, D. G., Schumann, C. M., & Nordahl, C. W. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2007.12.005 · Cited by 1,492 · cited 2×
“…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
Wisniewski, K. E., Wisniewski, H. M., & Wen, G. Y. (1985) · Annals of Neurology · doi:10.1002/ana.410170310 · Cited by 1,159 · cited 1×
“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).”
BackgroundThe pathological process underlying Alzheimer’s disease in individuals under thirty
Braak, H., & Del Tredici, K. (2011) · Acta Neuropathologica · doi:10.1007/s00401-010-0789-4 · Cited by 812
Hearing loss and cognition in the Baltimore Longitudinal Study of Aging.
Lin, F. R., Ferrucci, L., Metter, E. J., An, Y., Zonderman, A. B., & Resnick, S. M. (2011) · Neuropsychology · doi:10.1037/a0024238 · Cited by 696 · cited 1×
“Hearing loss in adults in the general population may be independently associated with lower test scores of memory and executive functioning (Gates et al., 2010; Lin et al., 2011).”
BackgroundAmyloid A4 Protein and Its Precursor in Down's Syndrome and Alzheimer's Disease
Rumble, B. A., Retallack, R. W., Hilbich, C., Simms, G., Multhaup, G., Martins, R. N., Hockey, A., Montgomery, P., Beyreuther, K. T., & Masters, C. L. (1989) · New England Journal of Medicine · doi:10.1056/nejm198906013202203 · Cited by 656
Salehi, A., Delcroix, J.-D., Belichenko, P. V., Zhan, K., Wu, C., Valletta, J. S., Takimoto-Kimura, R., Kleschevnikov, A. M., Sambamurti, K., Chung, P. P., et al. (2006) · Neuron · doi:10.1016/j.neuron.2006.05.022 · Cited by 543 · cited 1×
“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
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Items 201–225 of 225
Clinical Features of Adult-onset Epilepsy in Patients with Down Syndrome
Araki, K., Matsudaira, T., Ikeda, H., Usui, K., Terada, K., Obi, T., & Inoue, Y. (2015) · てんかん研究 · doi:10.3805/jjes.32.511
Bimstein, E., & Miskovich, C. (2018) · Journal of Clinical Pediatric Dentistry · doi:10.17796/1053-4628-42.4.11
Rodríguez-Ortiz, A., Villegas, J. C. M., Sánchez, A., Soto, J. M. S., Mina-Paz, Y., & García‐Vallejo, F. (2021) · Research Square · doi:10.21203/rs.3.rs-176627/v1
Down Syndrome, Obstetricians Should Know
Sung, J., Kim, S. H., Hong, S.-Y., Chang, C., Kim, Y., Jeon, J., Park, H., & Oh, S. (2021) · Perinatology · doi:10.14734/pn.2021.32.1.1
Stein, D. S., & Baumer, N. (2017) · Cambridge University Press eBooks · doi:10.1017/9781316216491.105
Jensen, K. M., & Bulova, P. D. (2016) · Springer eBooks · doi:10.1007/978-3-319-43827-6_10
Triplicated HSA21 genes and mtDNA on mitochondrial dysfunction
Ganguly, B. B. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-90456-8.00012-0
Age-Related Neurodevelopmental Features in Children with Joubert Syndrome
Scuderi, A., Prato, A., Dicanio, D., Spoto, G., Salpietro, V., Ceravolo, G., Granata, F., Farello, G., Iapadre, G., Zagaroli, L., et al. (2022) · Journal of Pediatric Neurology · doi:10.1055/s-0042-1759539
Investigating Brain Alterations in the Dp1Tyb Mouse Model of Down SyndromePreprint
Navacerrada, M. E. S., Kim, E., Siow, B. M., Ma, D., Gonzalez, L. R., Simmons, C., Hayward, D., Gibbins, D., Singh, N., Strydom, A., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.26.550698
Fahed, E., Msheik, A., Yazbeck, M., Rahal, M., Antoun, S., Geagea, C., & Younes, P. (2023) · eNeurologicalSci · doi:10.1016/j.ensci.2023.100480
“Individuals with DS typically have smaller brain volumes compared to those without the condition [2].”
BackgroundWITHDRAWN: Intricacies of aging and down syndrome
Kozlov, G., Franceschi, C., & Vedunova, M. V. (2024) · Aspects of Molecular Medicine · doi:10.1016/j.amolm.2024.100035
RetractedJensen, K. M., Bulova, P. D., & Santoro, S. L. (2024) · Springer eBooks · doi:10.1007/978-3-031-54281-7_30
Children with Down Syndrome: Improving Their Quality of Life
Uwaezuoke, S. N. (2024) · Springer eBooks · doi:10.1007/978-3-031-40858-8_268-1
Jandy, M., Hu, H., Liu, Y., & Bhattacharyya, A. (2025) · Springer eBooks · doi:10.1007/978-3-031-78611-2_7
Bartesaghi, R., Chen, X., Johnstone, A. D., Das, U., & Mobley, W. C. (2025) · Springer eBooks · doi:10.1007/978-3-031-89307-0_19
Torres, M. D., Rivera, I., & Busciglio, J. A. (2026) · Springer eBooks · doi:10.1007/978-3-031-96019-2_8
Infantile Epileptic Spasms Syndrome Complicating Mosaic Down‐Turner Syndrome: A Case Report
Shahrori, M., Nofal, K., Alkhawaja, H. H., Mohsen, W., & Alzamari, A. A. M. (2026) · Clinical Case Reports · doi:10.1002/ccr3.73505
Rossmassler, K., Timkovich, A. E., Niemeyer, B., Schade, K. A., Dunn, L. N., Harris, M. C., Harris, R. A., Chillamcherla, S., Rachubinski, A. L., Espinosa, J. M., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.20.751055
Stafstrom, C. E., & Shao, L. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15197471
“In Down syndrome, seizures have a bimodal age distribution, with about 40% of cases beginning in the first year of life and another 40% starting in adulthood [4,5].”
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., Thomas, W., Granholm, A.-C., Buhusi, M. C., Busciglio, J. A., et al. (2026) · Brain · doi:10.1093/brain/awag238
“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).”
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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