Cited by 225Down syndrome and intellectual disability researchAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

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Neurological phenotypes for Down syndrome across the life span

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Lott, Ira T.·2012·Progress in Brain Research

DOI 10.1016/b978-0-444-54299-1.00006-6PMC PMC3417824

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Abstract

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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Aerobic exercise training programmes for improving physical and psychosocial health in adults with Down syndrome
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
Retracted
Cerebellum 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).”
Background
Disorders of the Cerebellum: Ataxia, Dysmetria of Thought, and the Cerebellar Cognitive Affective Syndrome
Schmahmann, 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).”
Background
Neuroanatomy of autism
Amaral, 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).”
Background
Occurrence 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).”
Background
The 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).”
Background
Amyloid 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
Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration
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).”
Background
Cognitive 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.”
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Adiponectin Modulation by Genotype and Maternal Choline Supplementation in a Mouse Model of Down Syndrome and Alzheimer’s Disease
Alldred, M. J., Lee, S. H., & Ginsberg, S. D. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10132994 · Cited by 14
Timing of Muscle Response to a Sudden Leg Perturbation: Comparison between Adolescents and Adults with Down Syndrome
Valle, M. S., Cioni, M., Pisasale, M., Pantò, M. R., & Casabona, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081053 · Cited by 17
Weaker control of the electrical properties of cerebellar granule cells by tonically active GABAA receptors in the Ts65Dn mouse model of Down’s syndrome
Szemes, M., Davies, R. L., Garden, C. L. P., & Usowicz, M. M. (2013) · Molecular Brain · doi:10.1186/1756-6606-6-33 · Cited by 15
“; licensee BioMed Centra Commons Attribution License (http://creativec reproduction in any medium, provided the or decrease in neuron number and distorted neuronal morphology in the cerebellum, hippocampus and cerebral cortex [4].”
Background
Bexarotene Impairs Cognition and Produces Hypothyroidism in a Mouse Model of Down Syndrome and Alzheimer’s Disease
Vidal, V., Puente, A., García-Cerro, S., García‐Unzueta, M. T., Rueda, N., Riancho, J., & Martínez‐Cué, C. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.613211 · Cited by 16
“The cognitive alterations found in DS are primarily caused by prenatal changes in central nervous system growth and differentiation (Contestabile et al., 2007; Guidi et al., 2008; Haydar and Reeves, 2012; Lott, 2012; Rueda et al., 2012; Hibaoui et al., 2014; Stagni et al., 2018).”
Background
Age exacerbates abnormal protein expression in a mouse model of Down syndrome
Ahmed, M. M., Block, A., Tong, S., Davisson, M. T., & Gardiner, K. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.05.002 · Cited by 16
“There are, however, two features common to all with DS: some level of intellectual disability (ID) (Chapman and Hesketh 2000; Silverman 2007) and the development of the neuropathology of Alzheimer’s Diease (AD) at a young age (Head et al 2016; Lott 2012; Teipel and Hampel 2006).”
Background
Widespread cerebellar transcriptome changes in Ts65Dn Down syndrome mouse model after lifelong running
Walus, M., Kida, E., Rabe, A., Albertini, G., & Golabek, A. A. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.08.015 · Cited by 16
Down Syndrome Altered Cell Composition in Blood, Brain, and Buccal Swab Samples Profiled by DNA-Methylation-Based Cell-Type Deconvolution
Zhang, Z., Stolrow, H. G., Christensen, B. C., & Salas, L. A. (2023) · Cells · doi:10.3390/cells12081168 · Cited by 14
RCAN1 knockout and overexpression recapitulate an ensemble of rest-activity and circadian disruptions characteristic of Down syndrome, Alzheimer’s disease, and normative aging
Wong, H., Buck, J. M., Borski, C., Pafford, J., Keller, B. N., Milstead, R. A., Hanson, J. L., Stitzel, J. A., & Hoeffer, C. A. (2022) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-022-09444-y · Cited by 15
“However, an accelerated senescence phenotype is also characteristic of DS (Lott & Head, 2001; Lott, 2012), and general activity levels are well-known to decrease with aging [24, 36].”
Background
Beyond Trisomy 21: Phenotypic Variability in People with Down Syndrome Explained by Further Chromosome Mis-segregation and Mosaic Aneuploidy
Potter, H. (2016) · Journal of Down Syndrome & Chromosome Abnormalities · doi:10.4172/2472-1115.1000109 · Cited by 16
Disorders of the Developing Nervous System
Davis, L. E., & Richardson, S. P. (2015) · Springer eBooks · doi:10.1007/978-1-4939-2359-5_17 · Cited by 15
New Myrtenal–Adamantane Conjugates Alleviate Alzheimer’s-Type Dementia in Rat Model
Dragomanova, S., Lazarova, M. I., Munkuev, A. A., Суслов, Е. В., Volcho, K. P., Salakhutdinov, N. F., Bibi, A., Reynisson, J., Tzvetanova, E., Alexandrova, A., et al. (2022) · Molecules · doi:10.3390/molecules27175456 · Cited by 13
Neurodevelopmental wiring deficits in the Ts65Dn mouse model of Down syndrome
Jain, S., Watts, C. A., Chung, W. C. J., & Welshhans, K. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134569 · Cited by 13
Proposed diagnostic criteria for mild cognitive impairment in Down syndrome population
Esteba‐Castillo, S., García‐Alba, J., Rodriguez, E., Vaquero, L., Novell, R., Moldenhauer, F., & Castellanos, M. Á. (2021) · Journal of Applied Research in Intellectual Disabilities · doi:10.1111/jar.12959 · Cited by 12
Early impacts of modified food consistency on oromotor outcomes in mouse models of Down syndrome
Glass, T. J., Twadell, S., Valmadrid, L. C., & Connor, N. P. (2018) · Physiology & Behavior · doi:10.1016/j.physbeh.2018.11.031 · Cited by 12
“Down syndrome (DS) is caused by a trisomy of the 21st chromosome[1], and involves intellectual disability, differences of brain development, and differences in motor function [2, 3].”
Background
Deciphering the links between psychological stress, depression, and neurocognitive decline in patients with Down syndrome
Poumeaud, F., Mircher, C., Smith, P. J. K., Faye, P.-A., & Sturtz, F. G. (2021) · Neurobiology of Stress · doi:10.1016/j.ynstr.2021.100305 · Cited by 11
“This is of particular concern, as it can impair working memory and cause atrophy of the hippocampus, independently of the development of AD (Lott, 2012).”
Background
Neurodevelopmental disorders and microcephaly: how apoptosis, the cell cycle, tau and amyloid-β precursor protein APPly
Sokol, D. K., & Lahiri, D. K. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1201723 · Cited by 11
DYRK1A and Activity-Dependent Neuroprotective Protein Comparative Diagnosis Interest in Cerebrospinal Fluid and Plasma in the Context of Alzheimer-Related Cognitive Impairment in Down Syndrome Patients
Moreau, M., Carmona‐Iragui, M., Altuna, M., Dalzon, L., Barroeta, I., Vilaire-Meunier, M., Durand, S., Fortea, J., Rebillat, A., & Janel, N. (2022) · Biomedicines · doi:10.3390/biomedicines10061380 · Cited by 12
Trisomy 21-associated increases in chromosomal instability are unmasked by comparing isogenic trisomic/disomic leukocytes from people with mosaic Down syndrome
Rafferty, K. A., Archer, K. J., Turner, K. C., Brown, R. C., & Jackson‐Cook, C. K. (2021) · PLoS ONE · doi:10.1371/journal.pone.0254806 · Cited by 12
Targeting the GABAB Receptor for the Treatment of Epilepsy
Joshi, K., Cortez, M. A., & Snead, O. C. (2016) · The Receptors · doi:10.1007/978-3-319-46044-4_10 · Cited by 10
GIRK2 Channels in Down Syndrome and Alzheimer’s Disease
Kleschevnikov, A. M. (2022) · Current Alzheimer Research · doi:10.2174/1567205020666221223122110 · Cited by 10
Proteomic analysis of six- and twelve-month hippocampus and cerebellum in a murine Down syndrome model
Vacano, G. N., Gibson, D. S., Turjoman, A. A., Gawryluk, J. W., Geiger, J. D., Duncan, M. W., & Patterson, D. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.11.010 · Cited by 10
“These brain changes become more pronounced with age (Lott, 2012; Raz et al., 1995).”
Background
Enhanced GIRK2 channel signaling in Down syndrome: A feasible role in the development of abnormal nascent neural circuits
Kleschevnikov, A. M. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.1006068 · Cited by 9
“…Dierssen et al., 2009; Salehi et al., 2009; Faizi et al., 2011; Kleschevnikov et al., 2012a; Kleschevnikov et al., 2012c; Haydar and Reeves, 2012; Lott, 2012; Mohler, 2012; Rueda et al., 2012; Ruparelia et al., 2012; Lysenko et al., 2014; Martinez-Cue et al., 2014; Belichenko et al., 2016;…”
BackgroundInfluential
Vowel Production in Children and Adults With Down Syndrome: Fundamental and Formant Frequencies of the Corner Vowels
Vorperian, H. K., Kent, R. D., Lee, Y., & Buhr, K. A. (2023) · Journal of Speech Language and Hearing Research · doi:10.1044/2022_jslhr-22-00510 · Cited by 9
Lower urinary tract dysfunction in uncommon neurological diseases, Part II: A report of the Neuro-urology Promotion Committee of the International Continence Society
Sinha, S., Wachter, S. D., Welk, B. K., Sakakibara, R., Vrijens, D., Konstantinidis, C., Rapidi, C., Monteiro, L. M., Gomes, C. M., Drake, M. J., et al. (2023) · Continence · doi:10.1016/j.cont.2023.101043 · Cited by 9
Neuropathological findings in Down syndrome, Alzheimer’s disease and control patients with and without SARS-COV-2: preliminary findings
Granholm, A., Englund, E. M., Gilmore, A., Head, E., Yong, W. H., Perez, S. E., Guzman, S. J., Hamlett, E. D., & Mufson, E. J. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02743-9 · Cited by 11
“…a significant increase in average life span the last few decades but suffer from an increased incidence of early onset AD and associated amyloid [37], phospho-tau [38, 57, 72] and neurotransmitter cellular dysfunction [4, 11, 28, 32, 49, 54] compared to the general population [36, 79, 80].”
Background
Alterations in the Serotonin and Dopamine Pathways by Cystathionine Beta Synthase Overexpression in Murine Brain
London, J., Ndiaye, F. K., Bui, L. C., Souchet, B., Daubigney, F., Magnan, C., Luquet, S. H., Dairou, J., Janel, N., & Rouch, C. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1323-2 · Cited by 9
Neuronal Cell-Intrinsic Defects in Mouse Models of Down Syndrome
Chiotto, A. M. A., Migliorero, M., Pallavicini, G., Bianchi, F. T., Gai, M., Di Cunto, F., & Berto, G. E. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01081 · Cited by 9
“Much less is known about the alterations produced Frontiers in Neuroscience | www.frontiersin.org 4 October 2019 | Volume 13 | Article 1081 by HSA21 trisomy on cortical circuits, which are likely to significantly contribute to ID (Raz et al., 1995; Pinter et al., 2001; Lott, 2012).”
Background
Transcriptome and metabolome analysis of crGART, a novel cell model of de novo purine synthesis deficiency: Alterations in CD36 expression and activity
Mazzarino, R. C., Barešová, V., Zikánová, M., Duval, N., Wilkinson, T. G., Patterson, D., & Vacano, G. N. (2021) · PLoS ONE · doi:10.1371/journal.pone.0247227 · Cited by 8
Mitochondrial Dysfunction Correlates with Brain Amyloid Binding, Memory, and Executive Function in Down Syndrome: Implications for Alzheimer’s Disease in Down Syndrome
Beresford‐Webb, J., McAllister, C. J., Sleigh, A., Walpert, M., Holland, A. J., & Zaman, S. H. (2025) · Brain Sciences · doi:10.3390/brainsci15020130 · Cited by 10
“People with Down syndrome (DS) are at an exceptionally high risk of developing AD due to the triplication of chromosome 21 (Hsa21), which contains the APP gene, resulting in increased A β production [17–19].”
Behavioural Characteristics Related to Adaptive Functioning in Young Persons with Tuberous Sclerosis Complex, Down Syndrome and Fragile x Syndrome
Côté, V., Knoth, I. S., Lalancette, È., Lavergne, J.-A., Côté, L., Major, P., & Lippé, S. (2020) · Journal of Developmental and Physical Disabilities · doi:10.1007/s10882-020-09748-8 · Cited by 8
“ID is one of the widely known cognitive phenotype of this mutation (Lott 2012).”
BackgroundResultInfluential
Cell type characterization of spatiotemporal gene co-expression modules in Down syndrome brain
Seol, S., Kwon, J., & Kang, H. J. (2022) · iScience · doi:10.1016/j.isci.2022.105884 · Cited by 8
“We focused on these two regions because they have the widest range of developmental periods and are associated with cognition andmotor coordination in DS phenotypes.(16,17) Cell-type enrichment analysis on DEGs was conducted using published cell type-enriched gene lists.”
Method
Executive function in down syndrome children in Bogotá, Colombia
Manrique-Niño, J., Díaz-Forero, A., Vélez-van-Meerbeke, A., Ramírez-Guerrero, S., Flórez‐Esparza, G., & Talero‐Gutiérrez, C. (2020) · Heliyon · doi:10.1016/j.heliyon.2020.e05585 · Cited by 8
“In addition, the broad age range demonstrated by each group can be explained in terms of the neurological phenotypic variability observed in the DS population; this is a result of genetic expression, associated pathologies, and environmental influences (Chapman et al., 2000; Letourneau and Antonarakis, 2012; Lott, 201…”
Background
Down syndrome frontal cortex layer III and layer V pyramidal neurons exhibit lamina specific degeneration in aged individuals
Alldred, M. J., Ibrahim, K. W., Pidikiti, H., Chiosis, G., Mufson, E. J., Stutzmann, G. E., & Ginsberg, S. D. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01891-z · Cited by 7
“Triplication of HSA21 causes deficits in learning, language, and memory acquisition and consolidation on a spectrum of severity [17, 22, 47, 64, 67], however, the exact molecular mechanisms underlying these deficits remain underexplored.”
Analysis of microisolated frontal cortex excitatory layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with Down syndrome
Alldred, M. J., Pidikiti, H., Ibrahim, K. W., Lee, S. H., Heguy, A., Hoffman, G. E., Roussos, P., Wısnıewskı, T., Węgiel, J., Stutzmann, G. E., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02768-0 · Cited by 8
“Individuals with DS have a multitude of physical phenotypic abnormalities, and are intellectually impaired, with deficits in learning, language, and memory acquisition and consolidation [25, 38, 64, 83, 86].”
Down Syndrome
Esbensen, A. J., Schworer, E. K., & Hartley, S. L. (2024) · Contemporary clinical neuroscience · doi:10.1007/978-3-031-66932-3_13 · Cited by 14
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Washington, S. E., Cler, E., Lowery, C., & Stark, S. L. (2023) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12393 · Cited by 7
“The exclusion criteria were studies that: (1) included only children with DS, (2) investigated caregivers only, (3) investigated therapists/health professionals only, (4) did not measure and/or report functional outcomes, (5) did not investigate ADRD pathology and/or implications, and (6) were existing meta-analyses,…”
Background
Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome
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) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106336 · Cited by 7
“…MRS , 1 H spectroscopy; NAA , N -acetyl-aspartate; PCh , phosphocholine; PCr , phosphocreatine; ROI , regions of interest; SEM , standard error of the mean; Taur , taurine; WT , wild-type.. comorbidities such as diabetes, depression, and Alzheimer's disease (Antonarakis et al., 2020; Lott, 2012).”
Background
Intricacies of aging and Down syndrome
Kozlov, G., Franceschi, C., & Vedunova, M. V. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105794 · Cited by 6
In silico identification of critical proteins associated with learning process and immune system for Down syndrome
Kulan, H., & Dağ, T. (2019) · PLoS ONE · doi:10.1371/journal.pone.0210954 · Cited by 6
Stroke-Related Outcomes in Moyamoya Disease Compared with Moyamoya Syndromes: A Propensity-Matched Analysis
Wadhwa, A., Han, K., Ramirez‐Velandia, F., Alwakaa, O., Riordan, C. P., McNeil, E. P., Granstein, J. H., Taussky, P., Enríquez-Marulanda, A., & Ogilvy, C. S. (2024) · World Neurosurgery · doi:10.1016/j.wneu.2024.11.104 · Cited by 6
Neurological and neurodevelopmental manifestations in children and adolescents with Down syndrome
Baumer, N., & O’Neill, M. E. (2022) · International review of research in developmental disabilities · doi:10.1016/bs.irrdd.2022.09.004 · Cited by 7
D own syndrome and personalized medicine: Changing paradigms from genotype to phenotype to treatment
McCabe, L. L., & McCabe, E. R. B. (2012) · Congenital Anomalies · doi:10.1111/cga.12000 · Cited by 6
Development of Alzheimer’s disease in Down syndrome
García, O. A., Domínguez-de-la-Cruz, E., Luna-Martínez, I. G., Garnett-Carbajal, J. A., & Villegas-Piña, J. A. (2025) · Exploration of neuroscience · doi:10.37349/en.2025.1006104 · Cited by 4
Decrease in the T-box1 gene expression in embryonic brain and adult hippocampus of down syndrome mouse models.
Shimizu, R., Ishihara, K., Kawashita, E., Sago, H., Yamakawa, K., Mizutani, K.-I., & Akiba, S. (2020) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2020.12.026 · Cited by 3
The TRPM2 ion channel contributes to cytokine hyperproduction in a mouse model of Down Syndrome
Gally, F., Rao, D. M., Schmitz, C., Colvin, K. L., Yeager, M. E., & Perraud, A. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.09.025 · Cited by 5
“8 stress, which is inherent to DS (1,28,29) and would further exacerbate inflammation and increase TRPM2-activation.”
Background
Advancing Knowledge of Down Syndrome Brain Development and Function With Human Stem Cells
Bhattacharyya, A. (2020) · American Journal on Intellectual and Developmental Disabilities · doi:10.1352/1944-7558-125.2.90 · Cited by 5
“We know from histopathological analyses over the last 50 years that the structure of the Down syndrome brain is different than normal [5, 6].”
Background
Over‐expression of Dyrk1A affects bleeding by modulating plasma fibronectin and fibrinogen level in mice
Postic, G., Solarz, J., Loubière, C., Kandiah, J., Sawmynaden, J., Adam, F., Vilaire-Meunier, M., Léger, T., Camadro, J., Victorino, D. B., et al. (2023) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17817 · Cited by 4
Down syndrome: From development to adult life to Alzheimer disease
Butterfield, D. A., & Marzia Perluigi, A. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.10.374 · Cited by 5
“Indeed, DS individuals, typically between age of 40-50, show neuropathological hallmarks of Alzheimer disease (AD), including deposition of senile plaques containing amyloid beta-peptide (Aβ), neurofibrillary tangles composed of hyperphoshorylated tau, and cholinergic and serotonergic reduction [6, 7].”
Background
Hypotonia in the Newborn Infant
Laverty, C. G. (2025) · Pediatric Clinics of North America · doi:10.1016/j.pcl.2025.03.008 · Cited by 4
Frontal cortex pyramidal neuron expression profiles differentiate the prodromal stage from progressive degeneration across the Alzheimer's disease spectrum
Labuza, A., Alldred, M. J., Pidikiti, H., Malek‐Ahmadi, M. H., Lee, S. H., Heguy, A., Coleman, P. D., Chakrabarty, S., Chiosis, G., Mufson, E. J., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70395 · Cited by 3
A case report of atlanto-axial instability in a Down Syndrome patient
Jusabani, M. A., Rashid, S. M., Massawe, H., Howlett, W. P., & Dekker, M. C. J. (2018) · Spinal Cord Series and Cases · doi:10.1038/s41394-018-0139-7 · Cited by 4
Kognition bei Down-Syndrom: Entwicklung über die Lebensspanne und neuropsychologische Diagnostik im Erwachsenenalter
Loosli, S. V., Schmidt, L., Nübling, G., Wlasich, E., Prix, C., Danek, A., & Levin, J. (2021) · Fortschritte der Neurologie · Psychiatrie · doi:10.1055/a-1362-9868 · Cited by 5
“Hohe Retest-Reliabilität und konvergente Validität bei Menschen mit DS [79] [63, 79] fremdeinschätzung DSQIID – Dementia Screening Questionnaire for Individuals with Intellectual Disabilities Fremdbeurteilung zu Auffälligkeiten in Verhalten und Alltag, z. B. Gedächtnisverlust, Verwirrtheit, Verlust von Fähigkeiten, So…”
BackgroundInfluential
Long-term voluntary running modifies the levels of proteins of the excitatory/inhibitory system and reduces reactive astrogliosis in the brain of Ts65Dn mouse model for Down syndrome
Kida, E., Walus, M., Albertini, G., & Golabek, A. A. (2021) · Brain Research · doi:10.1016/j.brainres.2021.147535 · Cited by 4
The Effects of Different Exteroceptive Experiences on the Early Motor Repertoire in Infants With Down Syndrome
Yardımcı-Lokmanoğlu, B. N., Einspieler, C., Sırtbaş-Işık, G., Porsnok, D., Arıkan, Z., Livanelioğlu, A., & Mutlu, A. (2021) · Physical Therapy · doi:10.1093/ptj/pzab163 · Cited by 4
Psychomotor development in infants and young children with Down syndrome—A prospective, repeated measure, post‐hoc analysis
Sacco, S., Bouis, C., Gallard, J., Pichot, A., Blondiaux, E., Marey, I., Dorison, N., Sturtz, F. G., Cieuta‐Walti, C., Ravel, A., et al. (2021) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.62587 · Cited by 5
“…were carried out to identify factors that could impact GDQ. Neuronal loss and deceleration of brain growth, affecting the volume of frontal and temporal lobes, were observed as early as the second trimester of pregnancy and have been linked to cognitive deficits in children with DS (Lott, 2012).”
BackgroundInfluential
Integrated analysis of DNA methylation and RNA-sequencing data in Down syndrome
Zhang, J., Zhou, W., Liu, Y., & Li, N. (2016) · Molecular Medicine Reports · doi:10.3892/mmr.2016.5778 · Cited by 4
“In addition, patients with DS generally have shorter life expectancy (8,9).”
Abnormalities of Muscle Tone
Martino, D., Espay, A. J., Fasano, A. A., & Morgante, F. (2015) · Springer eBooks · doi:10.1007/978-3-662-48468-5_2 · Cited by 5
Gait variability as a marker of white matter integrity in individuals with Down syndrome
Leach, E. M., Powell, D. K., Glueck, A. C., Head, E., Ibrahim, M. W., Anderson-Mooney, A. J., Pelt, K. L. V., Harp, J. P., Schmitt, F. A., & Bahrani, A. A. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70407 · Cited by 3
Co‐occurring Down syndrome and SUCLA2‐related mitochondrial depletion syndrome
Couser, N., Marchuk, D. S., Smith, L. D., Arreola, A., Kaiser-Rogers, K., Muenzer, J., Pandya, A., Gucsavas-Calikoglu, M., & Powell, C. (2017) · American Journal of Medical Genetics. Part A · doi:10.1002/ajmg.a.38351 · Cited by 3
“In addition, while epilepsy is associated with Down syndrome, the seizures in patient 1 are more severe and less amenable to treatment thanwould be expected in a patient withDown syndrome alone (Lott, 2012).”
Background
Pons Anteroposterior and Cerebellar Vermis Craniocaudal Diameters in Fetuses With Down Syndrome
Erenel, H., & Madazlı, R. (2020) · Journal of Ultrasound in Medicine · doi:10.1002/jum.15382 · Cited by 3
“There is a wide range of neurologic manifestations related to structural abnormalities of brain development in DS.(18) Hypoplasia of the cerebellum and pons is thought to be associated with some neurologic consequences, such as hypotonia, motor coordination difficulties, articulatory speech disturbances, nystagmus, sl…”
Background
Parent Attitudes Toward Enhancing Cognition and Clinical Research Trials in Down Syndrome: A Mixed Methods Study
Christensen, K. M., Hojlo, M. A., Milliken, A. L., & Baumer, N. (2021) · Journal of Developmental & Behavioral Pediatrics · doi:10.1097/dbp.0000000000000900 · Cited by 3
“Down syndrome (DS), caused by the presence of all or part of an extra chromosome 21,(1) is the most common genetic cause of intellectual disability (ID).(2) In this new era of discovery in neurodevelopmental research, experimental treatments aim to target core characteristics and deficits in neurodevelopmental disorde…”
Background
Impact of Neonatal Body (Dis)Proportionality Determined by the Cephalization Index (CI) on Gross Motor Development in Children with Down Syndrome: A Prospective Cohort Study
Čeprnja, A. R., Pranić, S. M., Šunj, M., Kozina, T., Božić, J., & Kozina, S. (2022) · Children · doi:10.3390/children10010013 · Cited by 3
“Despite these difficulties, children with Down syndrome acquire the ability to rotate with trunk dissociation at an average age of 8 months, as do typical neonates [31].”
Background
Profiling hippocampal neuronal populations reveals unique gene expression mosaics reflective of connectivity-based degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer’s disease
Alldred, M. J., Ibrahim, K. W., Pidikiti, H., Lee, S. H., Heguy, A., Chiosis, G., Mufson, E. J., Stutzmann, G. E., & Ginsberg, S. D. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1546375 · Cited by 4
“…mild to moderate intellectual impairment, neurological deficits, including reduced numbers and size of neurons in the hippocampus, along with systemic peripheral deficits (Rachidi and Lopes, 2008; Chapman and Hesketh, 2000; Lott, 2012; Wisniewski, 1990; Freeburn and Munn, 2021; Emili et al., 2024).”
Aging of persons with neurodevelopmental disabilities
Anker, L. A., Chick, C. F., & Hallmayer, J. F. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-800136-3.00017-x · Cited by 5
Down Syndrome
Thurman, A., & Soriano, L. D. H. (2021) · Handbook of Pragmatic Language Disorders · doi:10.1007/978-3-030-74985-9_5
Down Syndrome
Ruparelia, A., & Mobley, W. C. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-398270-4.00005-7 · Cited by 4
Generation and Use of Transgenic Mice in Drug Discovery
Pavlovic, G., Brault, V., Sorg, T., & Hérault, Y. (2014) · Methods and principles in medicinal chemistry · doi:10.1002/9783527679348.ch06 · Cited by 3
The Health-Related Quality of Life of Adults with Down Syndrome
Graves, R. (2014) · doi:10.21007/etd.cghs.2014.0115 · Cited by 3
“This is consistent with findings of long-term explicit memory impairment in individuals with DS (Lott, 2012; Vicari, Bellucci, & Carlesimo, 2000).”
MethodResult
Impairment of CSF Egress through the Cribriform Plate plays an Apical role in Alzheimer’s disease EtiologyPreprint
Zaragoza, R., Miulli, D. E., Kashyap, S., Carson, T. A., Obenaus, A., Siddiqi, J., & Ethell, D. W. (2021) · medRxiv · doi:10.1101/2021.10.04.21264049 · Cited by 3
“Down syndrome (trisomy 21, DS) patients typically have brachycephaly (“pug-nose”) that impacts CP morphology, along with life-long cognitive impairment and a predisposition to AD-like pathology beginning in the 3rd decade (Lott, 2012).”
Background
Disrupted Neurogenesis from Basal Intermediate Precursor Cells Alters the Postnatal Neocortex in the TcMAC21 Mouse Model of Down Syndrome
Atak, Z., Srivastava, A., Gandhi, S., Park, E., Williams, J., Torii, M., & Haydar, T. F. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.0040-25.2025 · Cited by 2
Reported Impacts of Congenital Heart Disease on Functional Outcomes in Adults with Down Syndrome
Gaydos, S. S., Benitez, A. M., Nietert, P. J., McHugh, K. E., & Atz, A. M. (2025) · Pediatric Cardiology · doi:10.1007/s00246-025-03979-2 · Cited by 2
Down Syndrome
Torres, M. D., & Busciglio, J. A. (2014) · Springer eBooks · doi:10.1007/978-3-7091-0715-7_10 · Cited by 2
Síndrome de Down, cerebro y desarrollo
Molero‐Chamizo, A., & Urbina, G. N. R. (2013) · Summa Psicológica · doi:10.18774/448x.2013.10.44 · Cited by 2
Estrategias didácticas lúdicas para fortalecer la motivación lectora en estudiantes de preparatoria en una unidad educativa de Guayaquil, Ecuador 2022
Ortiz, S. (2023) · Ciencia Latina Revista Científica Multidisciplinar · doi:10.37811/cl_rcm.v7i4.7063 · Cited by 2
A Dive Into Cerebellar Dysfunction, Motor Deficits and GABAergic Signaling in Down Syndrome
Feely, S., Rodriguez, M. R., Shannon, A., Young, S., Rosales, J. P., & Kaur, G. (2025) · Cureus · doi:10.7759/cureus.79623 · Cited by 2
“Similarly, in the DS transgenic mouse model Ts65Dn, cerebellar volume, Purkinje cell (PC) linear density, and GC density were found to be significantly decreased [7,17,19-24].”
Influential
Neurological findings in a cohort of adults with down syndrome
Grotteschi, N., Rochat, M. J., Pollarini, V., Ghezzo, A., Pellegrini, C., Buonaura, G. C., Lodi, R., Tonon, C., Cortelli, P., Bacalini, M. G., et al. (2025) · Neurological Sciences · doi:10.1007/s10072-025-08195-7 · Cited by 3
Síndrome de Down, envejecimiento y lenguaje: consideraciones para el abordaje fonoaudiológico
Espina, M. G. (2017) · Revista Chilena de Fonoaudiología · doi:10.5354/0719-4692.2017.47558 · Cited by 2
Down syndrome: a model for chromosome abnormalities
Overk, C., & Mobley, W. C. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-85654-6.00007-1 · Cited by 4
BENEFITS OF INCORPORATING HIIT PROGRAMS FOR INDIVIDUALS WITH DOWN SYNDROME
Ware, M. E., McCully, K. K., & Feito, Y. (2020) · ACSMʼs Health & Fitness Journal · doi:10.1249/fit.0000000000000586 · Cited by 2
“Individuals with DS have unique neural pathways as a result of their phenotype (19).”
Background
Treatment of Chronic Dislocated Patella in a Skeletally Mature Down Syndrome Patient
Fong, J., Zeng, G. J., & Lee, K. H. (2022) · JBJS Case Connector · doi:10.2106/jbjs.cc.21.00710 · Cited by 2
Generation of integration-free Down syndrome and isogenic euploid human induced pluripotent stem cells
Nehra, S., Sharma, V., Umrani, M. R., & Singhal, N. (2023) · Stem Cell Research · doi:10.1016/j.scr.2023.103041 · Cited by 2
The impact of Mmu 17 non- Hsa 21 orthologous genes in the Ts65Dn mouse model of Down syndrome: the “gold standard” revisitedPreprint
Guedj, F., Kane, E., Bishop, L. A., Pennings, J. L. A., Hérault, Y., & Bianchi, D. W. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.23.509067 · Cited by 2
“The literature supports the presence of hyperactivity, delayed motor and speech development, defective hippocampal learning and memory and impaired executive function in individuals with DS, however, whether there are differences between males and females is poorly studied (64-68).”
Background
In Vitro Modeling of Down Syndrome Neurogenesis Using Human-Induced Pluripotent Stem Cells
Sharma, V., Chhawari, H., Joshi, P., Nehra, S., & Singhal, N. (2025) · Journal of Visualized Experiments · doi:10.3791/67382 · Cited by 1
Association of neurodegeneration, cognitive impairment, and short stature in Down syndrome; Could proinflammatory cytokines be the common factor?
Sadeghi, G., & Farjoo, M. H. (2025) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2025.111317 · Cited by 2
“In fact, they reduce the gonadal hormone stimulation, leading to a disruption in the balance between osteoclastic apoptosis and osteoblastic matrix formation.”
The cholinotrophic system in Down syndrome
Mufson, E. J., & Perez, S. E. (2025) · Handbook of clinical neurology · doi:10.1016/b978-0-443-19088-9.00017-2 · Cited by 1
Analysis of first-trimester maternal serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels as a potential non-invasive biomarker for fetal aneuploidy and NTDs
Karthick, E., Selvarajan, S., Kumar, D. S., Sowmya, K., & Sridharan, K. S. (2025) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/00045632251367280 · Cited by 1
“30 Further T21 affected infants are also prone for predisposition to Alzheimer ’ s disease and decreased neurocognition.”
Pre-Implantation factor (PIF) restores working memory and promotes microglial ramification in the adult Dp(16)1Yey mouse model of Down syndrome
Dard, R., Day, S., Faury, K., Ziga, J., Kandiah, J., Kassis, N., Rodriguez, Y., Vialard, F., Moreau, M., & Janel, N. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.178293 · Cited by 1
Prevalence, Spectrum, and Management of Thyroid Dysfunction in Children with Down Syndrome: A Retrospective Study from Southern Saudi Arabia
Alqahtani, Y. A., Shati, A. A., Alshaikh, A. A., Alshahrani, A. T., Qaed, S. B., Alqahtani, M., Alotaibi, O. A., Alharthi, M. O., Sarhan, M. H., Alrasheed, A. M., et al. (2025) · Children · doi:10.3390/children13010006 · Cited by 1
“…hypotonia contributes to motor delays, while patients also face an increased risk of seizures, early-onset Alzheimer’s disease due to Amyloid Precursor Protein (APP) gene triplication, refractive errors, and conductive hearing loss, necessitating comprehensive and lifelong specialty care [11–14].”
Implementation and acceptability of PUMA Playtime intervention for toddlers with Down syndrome: a feasibility study
Collimore, A. N., Sutter, E. N., Wilkerson, E., Baumer, N., & Iverson, J. M. (2026) · Disability and Rehabilitation Assistive Technology · doi:10.1080/17483107.2026.2716555 · Cited by 1
Neurofizjologiczne podłoże hipotonii mięśniowej w zespole Downa Neurophysiological basis of muscle hypotonia in Down syndrome
Olchowik, B., Sendrowski, K., Jakubiuk‐Tomaszuk, A., & Sobaniec, P. (2012) · Cited by 1
Chloride transporters in physiological brain development and neurodevelopmental disorders: The case of the Down syndrome
Savardi, A., Ziogas, I., Bolla, M., & Cancedda, L. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-815318-5.00021-2 · Cited by 1
Oxidative stress and mTOR in Down syndrome brain: Link to Alzheimer's dysmetabolism, neuropathology, and possible therapies
Marzia Perluigi, A., Domenico, F. D., & Butterfield, D. A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-818845-3.00009-8 · Cited by 1
Integrated Quantitative Neuro-Transcriptome Analysis of Several Brain Areas in Human Trisomy 21
Rodríguez-Ortiz, A., Montoya-Villegas, J. C., Sánchez, A., Soto, J. M. S., Mina-Paz, Y., & García‐Vallejo, F. (2022) · Genes · doi:10.3390/genes13040628 · Cited by 1
“Individuals with DS also frequently develop Alzheimer disease by the fourth decade [7], and the severity of their cognition impairment is highly variable [8-9].”
Background
Avances moleculares en el síndrome de Down y su posible aplicación en neurología
Ramos-Kuri, M., & Salgado-Sánchez, E. (2015) · Archivos de Neurociencias · doi:10.31157/an.v20i1.73 · Cited by 1
A Comprehensive Review on Down Syndrome Diagnosis and Associated Genes: Diagnosis of DS
Sattoju, N. (2023) · Clinical Medicine And Health Research Journal · doi:10.18535/cmhrj.v3i4.210 · Cited by 1
Exploring crystallized and fluid intelligence in down syndrome using graph theory
Lifshitz, H., Shnitzer‐Meirovich, S., Koslovsky, M., & Yozevitch, R. (2024) · Scientific Reports · doi:10.1038/s41598-024-74815-5 · Cited by 2
“Down syndrome (DS), a well-known genetic disorder occurring in approximately 1 in 800 live births, is characterized by an extra copy of chromosome 21 46 .”
Background
Síndrome de Down, cerebro y desarrollo Down syndrome, brain and development
Molero‐Chamizo, A., Urbina, G. N. R., & Urbina, R. (2013) · Cited by 1
Kidney, Pelvis, and Ureter
Sergi, C. M. (2020) · Springer eBooks · doi:10.1007/978-3-662-59169-7_6 · Cited by 1
Avaliação das habilidades funcionais de crianças e adolescentes com trissomia 21 (T21) e a relação com suas variáveis socioambientais e de saúde
Moriyama, C. H. (2022) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.6.2022.tde-18032022-144945 · Cited by 2

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)
DOI: 10.1016/b978-0-444-54299-1.00006-6
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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Neurological phenotypes for Down syndrome across the life span

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