Neurological phenotypes for Down syndrome across the life span

“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).”

“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).”

“…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).”

“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).”

“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).”

“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).”

“As recently reviewed (Lott and Dierssen, 2010), the cerebellum may be implicated in both cognition and affect in individuals with DS.”

“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).”

“There have been few studies of the cognitive consequences of obstructive sleep apnea in DS, but there is known to be an association of sleep apnea with lower IQ testing and behavioral difficulties (Bass et al., 2004; Melendres et al., 2004).”

“Magnetic resonance imaging (MRI) studies show an approximate 17% decrease in children with DS between 10 and 20years (Pinter et al., 2001a).”

“The Ts65Dn mouse model of DS appears to parallel the cholinergic degeneration found in adults with DS and dementia which is correlated with deficient release of acetylcholine from the hippocampus (Holtzman et al., 1996).”

“There have been few studies of the cognitive consequences of obstructive sleep apnea in DS, but there is known to be an association of sleep apnea with lower IQ testing and behavioral difficulties (Bass et al., 2004; Melendres et al., 2004).”

“However, other studies of subclinical hypothyroidism in the general population have failed to show significant neuropsychiatric problems (Baek et al., 2009).”

“Basal forebrain cholinergic neuronal degeneration has been reversed by intracerebroventricular injections of nerve growth factor (Cooper et al., 2001).”

“The brain is brachycephalic with a small cerebellum, simplified gyral appearance, and a narrow superior temporal gyrus (Coyle et al., 1986; Wisniewski, 1990).”

“Ultrastructural studies show that synaptic density, synaptic length, and the contact zones between neurons are abnormal (Raz et al., 1995) (Fig.”

“Obstructive sleep apnea occurs in over half of children with DS aged 2–4years and is related to otolaryngological problems associated with the disorder (Shott et al., 2006).”

“Lack of balance in the metabolism of free radicals may have a direct role in the development of neuropathological changes of AD in DS (Zigman and Lott, 2007).”

“An analysis of cell proteins expressed in various stages of the cell cycle has shown a prolongation of the G2 phase of the cell cycle, the last step in interphase prior to mitotic division (Contestabile et al., 2007).”

“…number of animals in a short time, genetic engineering for individual genes, control for genetic background, low cost of screening, ability to study both developing and mature subjects, modeling therapeutic interventions, and the lack of postmortem delays (Patterson, 2009; Salehi et al., 2007).”

“In fetuses with DS, an analysis of cell phenotypes shows less reduction in astrocytes as compared to neurons (Guidi et al., 2008).”

“Seizures in the temporal lobe may damage hippocampal circuitry, a situation which is worsened by the toxic accumulation of amyloid-b peptides seen in Alzheimer’s disease (AD) (Noebels, 2011).”

“This raises the prospect that treatment to reduce the level of APP gene expression may lessen the severity of cognitive decline in the dementia associated with DS (Megarbane et al., 2009).”

“age-matched peers, children with DS show higher rates of inattention, oppositional behaviors, and impulsivity (Dykens, 2007).”

“Memory loss in old age is strongly correlated with a decline in the levels of acetylcholine (Mori et al., 2002; White and Ruske, 2002).”

“Immune dysfunction in DS has been associated with the occurrence of AD (Kusters et al., 2009).”

“The brain is brachycephalic with a small cerebellum, simplified gyral appearance, and a narrow superior temporal gyrus (Coyle et al., 1986; Wisniewski, 1990).”

“…may reflect an underlying problem in social interactions in some children with DS. Recent use of screening tools and standardized diagnostic measures in 123 children with DS has yielded a prevalence of 18% for autistic spectrum disorders and 7% for the diagnosis of autism (DiGuiseppi et al., 2010).”

“In a study utilizing a polyphenol diet, the major features of the transgenic phenotype were rescued (Guedj et al., 2009).”

“These anatomic findings have also been seen by voxel-based morphometric MRI studies of the brain in children and adults with DS (Pinter et al., 2001a,b; Teipel et al., 2003, 2004; White and Alkire, 2003).”

“Overexpression of DYRK1A may exert its effect on apoptosis and cell survival (Tejedor and Hammerle, 2011).”

“The parahippocampal and inferior temporal gyri demonstrate b-amyloid staining as young as 8years of age with subsequent accumulation in the CA-1/subiculum, dentate molecular layer, and the remainder of the hippocampal area (Leverenz and Raskind, 1998).”

“DNA damage, repair, and abnormal dynamic flux have been linked to oxidative stress and AD-type neurodegeneration (Martin, 2008; Vasudevaraju et al., 2008).”

“Findings here show impaired working memory, attention, vigilance, and the ability to carry out simulated activities in the face of obstructive sleep apnea (Jackson et al., 2011).”

“The compound is also a noncompetitive inhibitor of the serotonin receptor 5HT3 (Rammes et al., 2001).”

“Nonpharmacological interventions such as cognitive therapy and exercise have shown some improvements in individuals with AD within the general population (Buschert et al., 2010; Littbrand et al., 2011).”

“Magnetic resonance imaging (MRI) studies show an approximate 17% decrease in children with DS between 10 and 20years (Pinter et al., 2001a).”

“Cognitive development in DS has been described elsewhere in this volume (Edgin et al., 2010a).”

“Individuals with DS are prone to develop hyperopia, strabismus, blepharitis, cataracts, and glaucoma (Esbensen, 2010; van Allen et al., 1999).”

“Individuals with DS over age 45 years are more likely to develop dementia than those with seizures onset at younger ages (Menendez, 2005).”

“Moreover, careful morphological studies of postmortem brain of individuals with autism have shown subgroup variability in neuronal density, providing a cytoarchitectonic foundation for brain heterogeneity (Simms et al., 2009).”

“Cortical-inhibition circuitries regulating neural plasticity has been postulated as related to the pathogenesis of brain functioning in both DS and autistic disorder (Baroncelli et al., 2011).”

“The occurrence is bimodal with 40% having seizures before 1year of age—generally infantile spasms—and with 40% developing seizures after the third decade, generally tonic–clonic or myoclonic in manifestation (Pueschel et al., 1991).”

“Development of a GABA-A benzodiazepine receptor inverse agonist that is selective for the a5-subtype receptor appears to eliminate the convulsant propensity while maintaining cognitive restorative properties (Braudeau et al., 2011a,b).”

“The anatomic locus for hypotonia in DS appears to be the cerebellum, a structure which shows hypocellularity due to impairment in the granular and periventricular zones during fetal development (Guidi et al., 2011).”

“Children with DS may be at a lower risk for significant behavioral comorbidities in that they show a lower profile of maladaptive behaviors compared to children with other intellectual disabilities (Dykens and Kasari, 1997; Stores et al., 1998).”

“Mitochondrial control region mutations are seen in the brains of individuals with DS and dementia as well as AD (Coskun et al., 2010) (Fig.”

“The impairments resulting from hypothyroidism are primarily mnemonic rather than a reflection of general cognitive slowing and suggest a disruption of normal hippocampal function or connectivity (Correia et al., 2009).”

“…to the areas of brain dysgenesis that are commonly part of the neuroanatomic presentation in DS. Areas of focal cortical dysplasia may be associated with epilepsy in the general population related to the location and size of the lesions (Andrade, 2009; Leventer et al., 2008; Sisodiya et al., 2009).”

“These anatomic findings have also been seen by voxel-based morphometric MRI studies of the brain in children and adults with DS (Pinter et al., 2001a,b; Teipel et al., 2003, 2004; White and Alkire, 2003).”

“The challenge of therapeutic trials in DS is similar to those reviewed for AD in the general population for which pleiotropic interventions have been recommended (Frautschy and Cole, 2010).”

“Memantine is an antagonist of N-methyl D-aspartate receptor and appears to exert a positive effect on cognitive function by reducing oxidative damage and upregulating brain-derived neurotrophic factor (Marvanova et al., 2001).”

“Nonpharmacological interventions such as cognitive therapy and exercise have shown some improvements in individuals with AD within the general population (Buschert et al., 2010; Littbrand et al., 2011).”

“Unexplainably, the parahippocampal gyrus may be larger than normal in DS (Kesslak et al., 1994).”

“It appears that children with DS have better seizure control compared to other patients with symptomatic infantile spasms, and early initiation of appropriate treatment may contribute to the prevention of late seizure development and better developmental outcome (Arya et al., 2011).”

“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).”

“Difficulties in word recognition, oral language, nonverbal ability, and working memory may underline reading comprehension problems in both DS and autistic spectrum disorders (Ricketts, 2011).”

“Treatment with glutamate receptor antagonists may help repress APP and serve as a therapeutic target for AD (Sokol et al., 2011).”

“The low levels of physical activity in DS result in a higher body mass index, lower levels of lean mass, and reduced bone mass-related parameters, which, in turn, may affect cardiovascular strength capacities (Gonzalez-Aguero et al., 2010).”

“Oxidative stress may be a common pathogenetic mechanism across multiple genetic disorders including ataxia-telangiectasia, Fanconi anemia, Werner syndrome, and DS (Lloret et al., 2011).”

“from hypotonia is associated with a delay in motor development (Carr, 1970; Melyn and White, 1973).”

“A complex I deficit has been described in mitochondria from skin fibroblasts in DS that produces free radicals associated with oxidative stress (Valenti et al., 2011).”

“Methylation, which is a necessary event in mitochondrial functioning, is impaired in DS (Infantino et al., 2011).”

“The hypotonia induces difficulty in postural control such that an individual with DS is focused on overcoming a lack of equilibrium compared to controls and this necessitates a different strategy in motor development (Rigoldi et al., 2011).”

“Other genes on chromosome 21 that have been implicated in the pathogenesis of AD include superoxide dismutase, Ets-2 transcription factors, DS critical region stress-inducible factor, b-site APP cleaving enzyme, and S100b and dual-specificity tyrosine phosphorylation-regulation kinase 1A (DYRK1A) (Head and Lott, 2004).”

“An ongoing conundrum for the use of agents to improve cognitive functioning is the interaction of the drug with existing medication, an issue that has been explored in the neuropsychiatric literature and which can be addressed partially through preclinical studies (Wallace et al., 2011).”

“Cognitive development in DS has been described elsewhere in this volume (Edgin et al., 2010a).”

“Weakness in language abilities of children with DS has been noted (Dykens et al., 2006; Fidler et al., 2005; Rondal et al., 2003).”

“This may be an example of the disruption of developmental timing and homeostasis that occurs in DS and possibly other examples of aneuploidy (Pritchard and Kola, 1999).”

“Cleland (Cleland et al., 2010) has challenged the stereotypical perception that individuals with DS are highly social and have excellent “people” skills.”

“…aspects from strategies using mixed physical activity programs, well-conducted research examining long-term physical outcomes, adverse effects, psychosocial outcomes, and costs is required before informed practice decisions can be made (Andriolo et al., 2010; Shields and Taylor, 2010).”

“Hypotonia in DS is often associated with low levels of physical activity with the result of decreased bone mass accrual and predisposition to fractures (Hawli et al., 2009).”

“These anatomic findings have also been seen by voxel-based morphometric MRI studies of the brain in children and adults with DS (Pinter et al., 2001a,b; Teipel et al., 2003, 2004; White and Alkire, 2003).”

“Put slightly differently, deviant growth trajectories in autism may lead to developmental disruption of established patterns of functional connectivity (Lewis and Elman, 2008).”

“Differences are cited in developing task-oriented strategies for problem solving and difficulties with goaldirected behaviors (Glenn et al., 2001; Jahromi et al., 2008; Kasari and Freeman, 2001; Wishart, 1993; Wishart and Manning, 1996).”

“There are many genes in the mouse that are orthologous to genes on human chromosome 21 (Das and Reeves, 2011).”

“This reduction in brain size appears in 4–5-month fetuses and progresses during the last 3months of gestation (Engidawork and Lubec, 2003; Guihard-Costa et al., 2006).”

“Differences are cited in developing task-oriented strategies for problem solving and difficulties with goaldirected behaviors (Glenn et al., 2001; Jahromi et al., 2008; Kasari and Freeman, 2001; Wishart, 1993; Wishart and Manning, 1996).”

“Seizures appear to be associated with rapid cognitive decline in demented individuals with DS (Lott et al., 2012).”

“This is over a 10-fold increase compared to the general population (Lowenthal et al., 2007).”

“While it has been thought that individuals with DS are more prone to depression than those with other forms of intellectual disability, a recent meta-review does not support the putative increased prevalence of depression in trisomy 21 (Walker et al., 2011).”

“The ligamentous laxity resulting from hypotonia is associated with a delay in motor development (Carr, 1970; Melyn and White, 1973).”

“In patients with mild cognitive impairment in the general population, sleep apnea was associated with an increase in language dysfunction (Kim et al., 2011).”

“Neurite sprouting has been seen in approximately the same areas by postmortem examination (Haier et al., 2003; Head et al., 2007).”

“Dysregulated chromosome 21 genes in cortical neural progenitor cells from individuals with DS lead to elevated levels of S100b-induced radical oxygen species along with loss of the water channel aquaporin 4, causing an increase in programmed cell death (Lu et al., 2011).”

“Histopathological brain lesions include gliosis, demyelination, spongiform transformation of neurons, and vasculitis involving venules (Vincent and Crino, 2011).”

“In a study of nonpsychiatric health factors leading to psychiatric decompensation in adults with DS, 40% were found to have a significant comorbid medical condition considered causal in the behavioral decline (Charlot et al., 2011).”

“This reduction in brain size appears in 4–5-month fetuses and progresses during the last 3months of gestation (Engidawork and Lubec, 2003; Guihard-Costa et al., 2006).”

“Likewise, a trial of donepezil in children and adolescents with DS failed to demonstrate cognitive benefit (Kishnani et al., 2010).”

“indicators of conversion to AD, possibly reflecting compartmentalization of b-amyloid peptides in the brain (Schupf et al., 2010).”

“The precise effect of the above-described cytoarchitectonic abnormalities on cognitive development in DS is not clear, in part due to individual variation in performance measures with age (Couzens et al., 2011; Tsao and Kindelberger, 2009).”

“In a small study of children with DS, sleep apnea was associated with difficulties in visual-perceptual skills involving the right hemisphere (Andreou et al., 2002).”

“After controlling for level of intellectual disability (mild, moderate, severe) and the presence or absence of dementia, there was an improved prediction of neuropsychological scores by plasma levels of b-amyloid (Head et al., 2011).”

“The immune dysfunction begins in children with DS as reflected in abnormalities seen on the analysis of peripheral T-cell subsets, natural killer cells, and serum cytokines (Cetiner et al., 2010).”

“The precise effect of the above-described cytoarchitectonic abnormalities on cognitive development in DS is not clear, in part due to individual variation in performance measures with age (Couzens et al., 2011; Tsao and Kindelberger, 2009).”

“Measures of behavioral dysfunction in the same study are consistent with age-related progression of AD neuropathology in this population (Nelson et al., 2011).”

“Neurite sprouting has been seen in approximately the same areas by postmortem examination (Haier et al., 2003; Head et al., 2007).”

“…number of animals in a short time, genetic engineering for individual genes, control for genetic background, low cost of screening, ability to study both developing and mature subjects, modeling therapeutic interventions, and the lack of postmortem delays (Patterson, 2009; Salehi et al., 2007).”

“Weakness in language abilities of children with DS has been noted (Dykens et al., 2006; Fidler et al., 2005; Rondal et al., 2003).”

“In individuals with DS, the excessive laxity of the posterior transverse ligament which attaches the odontoid bone to C1 appears to be the most common cause of atlanto-axial subluxation although there is no universal agreement on this point (Merrick et al., 2000).”

“Memory loss in old age is strongly correlated with a decline in the levels of acetylcholine (Mori et al., 2002; White and Ruske, 2002).”

“Senile myoclonic epilepsy appears to be a common manifestation of dementia in DS (De Simone et al., 2010).”

“…aspects from strategies using mixed physical activity programs, well-conducted research examining long-term physical outcomes, adverse effects, psychosocial outcomes, and costs is required before informed practice decisions can be made (Andriolo et al., 2010; Shields and Taylor, 2010).”

“In subclinical and overt hypothyroidism in the general population, deficits are noted in spatial, associative, and verbal memory with some amelioration by thyroid replacement therapy (Kramer et al., 2009).”

“4b) (Landt et al., 2011).”

“Multiple genes that are upregulated in trisomy 21 may contribute to transcriptional disruption and increase the liability to oxidative stress (Lockstone et al., 2007; Strydom et al., 2009).”

“In the general population, the drug appears to alleviate some symptoms of AD (Ferris, 2003).”

“Development of a GABA-A benzodiazepine receptor inverse agonist that is selective for the a5-subtype receptor appears to eliminate the convulsant propensity while maintaining cognitive restorative properties (Braudeau et al., 2011a,b).”

“…to the areas of brain dysgenesis that are commonly part of the neuroanatomic presentation in DS. Areas of focal cortical dysplasia may be associated with epilepsy in the general population related to the location and size of the lesions (Andrade, 2009; Leventer et al., 2008; Sisodiya et al., 2009).”

“There is an association of several biomarkers for AD for in the general population that are also seen in individuals with DS including APOE, SORL1, RUNX1, BACE1, and ALDH18a1 (Patel et al., 2011).”

“These findings suggest that the amyloid precursor protein (APP), which is overexpressed in DS, may mediate this seizure susceptibility through the glutamate receptor (Westmark et al., 2009, 2010).”

“Molecular dating techniques have shown that b-amyloid is deposited in the superficial layers of the frontal cortex in DS with subsequent transition to deeper cortical areas with age (Azizeh et al., 2000).”

“Differences are cited in developing task-oriented strategies for problem solving and difficulties with goaldirected behaviors (Glenn et al., 2001; Jahromi et al., 2008; Kasari and Freeman, 2001; Wishart, 1993; Wishart and Manning, 1996).”

“Individuals with DS and mice with partial trisomy contain an extra copy of the DYRK1A gene and this appears to be associated with changes in brain morphogenesis (Dierssen and de Lagran, 2006; Toiber et al., 2010).”

“However, in DS, there appears to be no consistent or compelling evidence for efficacy of acetylcholinesterase inhibitors including donepezil, galantamine, and rivastigmine in preventing the cognitive decline associated with dementia (Mohan et al., 2009a–d).”

“Children with DS appear to present memory profiles that are distinct from other Williams and fragile-X syndromes in that DS is characterized by good immediate visual memory and rapid phonological retrieval with poor verbal working memory skills (Conners et al., 2011; Edgin et al., 2010b).”

“Infants with DS show a sequence of motor development similar to typically developing toddlers but a lower rate of motor milestone acquisition (Agiovlasitis et al., 2009).”

“Hashimoto’s encephalopathy, an autoimmune complication of hypothyroidism, which presents with myoclonus, neuropsychiatric symptoms, cognitive decline, and stroke-like episodes, has been described in DS (Brodtmann, 2009; Popova et al., 2008).”

“There is a high rate of EEG abnormalities in DS without the recognition of clinical seizures (40%); therefore, EEG findings do not correlate with outcome (Smigielska-Kuzia et al., 2009).”

“An encouraging aspect of the mouse study was the reversal of deficits in the 4-month-old Ts65Dn mouse when treated with an acetylcholinesterase inhibitor (Chang and Gold, 2008).”

“When Lennox–Gastaut syndrome occurs in DS, the onset is usually later than seen in the typical population and may be associated with reflex seizures (Ferlazzo et al., 2009).”

“However, in DS, there appears to be no consistent or compelling evidence for efficacy of acetylcholinesterase inhibitors including donepezil, galantamine, and rivastigmine in preventing the cognitive decline associated with dementia (Mohan et al., 2009a–d).”

“These findings have been translated into a clinical trial of memantine for improving cognitive functioning in young adults with DS which is currently underway (Costa, 2011).”

“However, in DS, there appears to be no consistent or compelling evidence for efficacy of acetylcholinesterase inhibitors including donepezil, galantamine, and rivastigmine in preventing the cognitive decline associated with dementia (Mohan et al., 2009a–d).”

“In the Ts65Dn mouse, oral treatment with memantine improved spatial learning in the Morris water maze task (Rueda et al., 2008).”

“However, in DS, there appears to be no consistent or compelling evidence for efficacy of acetylcholinesterase inhibitors including donepezil, galantamine, and rivastigmine in preventing the cognitive decline associated with dementia (Mohan et al., 2009a–d).”

“Administration of drugs that inhibit the breakdown of acetylcholine (donepezil) has reversed the memory deficits associated with aging and AD in the general population (Rusted et al., 1994; van Reekum et al., 1997).”

“DNA damage, repair, and abnormal dynamic flux have been linked to oxidative stress and AD-type neurodegeneration (Martin, 2008; Vasudevaraju et al., 2008).”

“Differences are cited in developing task-oriented strategies for problem solving and difficulties with goaldirected behaviors (Glenn et al., 2001; Jahromi et al., 2008; Kasari and Freeman, 2001; Wishart, 1993; Wishart and Manning, 1996).”

“Urinary markers of oxidative stress are increased in adolescents and adults with DS (Campos et al., 2010).”

“However, in demented adults with DS, APOE4 allele was associated with higher Ab40 but not Ab42.”

“The instability in trunk control may be linked to atypical finger grasping patterns (Jover et al., 2010).”

“Evaluation of thyroid functioning has been a part of health care guidelines for both children and adults with DS (Virji-Babul et al., 2007).”

“Electroclinical characteristics of seizures in adults with DS have included progressive slowing of background activity with frontal sharp and slow waves while those with myoclonic epilepsy typically display generalized spike and slow wave discharges (Vignoli et al., 2011).”

“Socialization and competence in daily living skills appear to improve through age 30years in DS (Dressler et al., 2010).”

“Hashimoto’s encephalopathy, an autoimmune complication of hypothyroidism, which presents with myoclonus, neuropsychiatric symptoms, cognitive decline, and stroke-like episodes, has been described in DS (Brodtmann, 2009; Popova et al., 2008).”

“Caspase activation, another precursor of programmed cell death, occurs in association with amyloid plaques and neurofibrillary tangles in DS (Head et al., 2002).”

“In a quantitative movement protocol measuring functional mobility, individuals with DS appeared to show longer durations of execution across all of the standardized tasks (Galli et al., 2010).”

“…carbon 11-labeled Pittsburgh Compound B or a subject with DS and AD (top) and a control without DS Neurology, Nelson LD et al., Positron emission tomogrpahy , 2011, June; 68(6):768–774 with permission from American S, old DS, and AD showing binding characteristics. lines (Dogliotti et al., 2010).”

“An alternative explanation may relate to the DYRK1A which is located on chromosome 21 and regulates multiple genes that may contribute to deregulation of neural pathways responsible for dementia (Ji et al., 2010).”

“Weakness in language abilities of children with DS has been noted (Dykens et al., 2006; Fidler et al., 2005; Rondal et al., 2003).”

“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).”