Alzheimer's disease in Down syndrome: neurobiology and risk

Down syndrome (DS) is characterized by increased mortality rates, both during early and later stages of life, and age-specific mortality risk remains higher in adults with DS compared with the overall population of people with mental retardation and with typically developing populations. Causes of increased mortality rates early in life are primarily due to the increased incidence of congenital heart disease and leukemia, while causes of higher mortality rates later in life may be due to a number of factors, two of which are an increased risk for Alzheimer's disease (AD) and an apparent tendency toward premature aging. In this article, we describe the increase in lifespan for people with DS that has occurred over the past 100 years, as well as advances in the understanding of the occurrence of AD in adults with DS. Aspects of the neurobiology of AD, including the role of amyloid, oxidative stress, Cu/ZN dismutase (SOD-1), as well as advances in neuroimaging are presented. The function of risk factors in the observed heterogeneity in the expression of AD dementia in adults with DS, as well as the need for sensitive and specific biomarkers of the clinical and pathological progressing of AD in adults with DS is considered.     

An experimental approach to detecting dementia in Down syndrome: a paradigm for Alzheimer's disease

Measures developed from animal models of aging may detect dementia of the Alzheimer's type in a population at-risk for Alzheimer's disease (AD). Although, by middle age, individuals with Down syndrome (DS) show an extraordinarily high prevalence of AD-type pathology, their severe idiopathic cognitive deficits tend to confound the clinical diagnosis of AD. The current study was designed to improve detection of AD in DS by using measures of learning and memory derived from animal models of aging. Adults with DS (N=34) were assessed and reassessed (n=19) approximately one year later using stimulus-response (S-R) test methods derived from experimental literature, as well as standardized informant-based tests. Results demonstrated high validity and reliability of select tests. The implication of early symptom detection in a population at-risk for AD-type dementia was discussed in terms of potential brain regions of interest.     

The missing link between faces and names: Evidence from Alzheimer's disease patients

Retrieval of proper names is a cause of concern and complaint among elderly adults and it is an early symptom of patients suffering from neurodegenerative diseases such as Alzheimer's disease (AD). While it is well established that AD patients have deficits of proper name retrieval, the nature of such impairment is not yet fully understood. Specifically, it is unknown whether this deficit is due to a degradation of the links between faces and proper names, or due to deficits in intentionally accessing and retrieving proper names from faces. Here, we aim to investigate the integrity of the links between famous faces and proper names in AD while minimizing the impact of the explicit retrieval. We compare the performances of AD patients and elderly controls in a face-name priming task. We assess the integrity of the link between faces and names at two different levels: identity level - the name and face belong to the same person; and semantic level - the name and face belong to the same category (e.g., politicians). Our results reveal that AD patients compared with controls show intact semantic priming but reduced priming for person identity. This suggests that the deficits in intentionally retrieving proper names in AD are the result of a partial disruption of the network at the identity level, i.e., the links between known faces and proper names.     

Picture priming in normal aging and Alzheimer's disease

The present study investigated age invariance for naming pictures and whether implicit memory is spared in Alzheimer's disease (AD). During the study phase, young adults, AD patients, and older controls were shown outlines of familiar pictures. After a distracter task, implicit memory was assessed incidentally. The results showed similar visual priming for the three groups, although young adults responded faster than the two older groups. Moreover, the number of errors was smaller for studied than for non-studied pictures. This pattern of results was repeated across the three groups, although AD patients produced more errors than young adults and older controls, and there were no differences between these latter groups. These results confirmed previous visual and haptic findings showing unimpaired perceptual priming in normal aging and AD patients when implicit memory is assessed using identification tasks. These results are interpreted from a cognitive neuroscience perspective.     

Language and communication development in Down syndrome

Although there is considerable variability, most individuals with Down syndrome have mental retardation and speech and language deficits, particularly in language production and syntax and poor speech intelligibility. This article describes research findings in the language and communication development of individuals with Down syndrome, first briefly describing the physical and cognitive phenotype of Down syndrome, and two communication related domains-hearing and oral motor skills. Next, we describe language development in Down syndrome, focusing on communication behaviors in the prelinguistic period, then the development of language in children and adolescents, and finally language development in adults and the aging period. We describe language development in individuals with Down syndrome across four domains: phonology, semantics, syntax, and pragmatics. Wethen suggest strategies for intervention and directions for research relating to individuals with Down syndrome.     

Neuronal changes in normal human aging and Alzheimer's disease

This article discusses age-related changes in brain weight, total number of cortical neurons, cortical dendrites, spine, and synapse density. The conclusion is that the present outlook is less grim than it was 30 years ago. Age-related reduction appears to be specific to brain region and cortical layer rather than a general feature. In addition, we describe a different pattern of changes that occur in Alzheimer's disease patients. This review concludes that the association cortices in particular are affected in aging and Alzheimer's disease and that the primary visual and somatosensory cortices are relatively spared.     

Short- and long-term implicit memory in aging and Alzheimer's disease

Implicit memory processes were investigated via picture naming in healthy young and older adults and in persons with mild Alzheimer's disease (AD). Repetition priming in picture-naming was intact in all groups over the course of a short retention interval (seconds), and only the AD group revealed a deficit over a longer interval (72 hours). In addition, the AD group showed impaired procedural memory, with no benefit of practice on picture-naming. Impaired long-term priming was related to severity of AD. Both theoretical and methodological implications are discussed.     

Vision-fair neuropsychological assessment in normal aging, Parkinson's disease and Alzheimer's disease

We examined performance of healthy older and younger adults and individuals with Alzheimer's disease (AD) and Parkinson's disease (PD) on digit cancellation, a task putatively sensitive to cognitive impairment, but possibly affected by visual impairment, particularly in contrast sensitivity. Critical contrast thresholds were established to create custom stimulus arrays that were proximally matched across individuals. Age- and PD-related differences in search were fully accounted for by the sensory deficit. Increased contrast benefited AD patients, but could not override cognitive impairment. We conclude that visually fair neuropsychological testing can effectively compensate for normal age- and PD-related visual changes that affect cognitive performance. (PsycINFO Database Record (c) 2012 APA, all rights reserved).     

Effects of normal aging and Alzheimer's disease on emotional memory

Recall is typically better for emotional than for neutral stimuli. This enhancement is believed to rely on limbic regions. Memory is also better for neutral stimuli embedded in an emotional context. The neural substrate supporting this effect has not been thoroughly investigated but may include frontal lobe, as well as limbic circuits. Alzheimer's disease (AD) results in atrophy of limbic structures, whereas normal aging relatively spares limbic regions but affects prefrontal areas. The authors hypothesized that AD would reduce all enhancement effects, whereas aging would disproportionately affect enhancement based on emotional context. The results confirmed the authors' hypotheses: Young and older adults, but not AD patients, showed better memory for emotional versus neutral pictures and words. Older adults and AD patients showed no benefit from emotional context, whereas young adults remembered more items embedded in an emotional versus neutral context.     

The effect of Alzheimer's disease and aging on conceptual combination

Alzheimer's disease (AD) subjects, healthy elderly, and young adults interpreted a series of novel noun-noun expressions composed of familiar object words. Subjects interpreted each item by selecting one of three possible definitions: a definition in which the referents of each noun were associated together in a particular context (e.g., rabbit cat: a cat that is raised by rabbits); a definition based on integrating the semantic attributes from each noun into a single referent (e.g., rabbit cat: a cat that has long ears and hops); and a semantic foil. The results show that the AD subjects selected significantly fewer integrational definitions and significantly more foils than healthy elderly subjects. Healthy elderly participants were also found to select significantly more foil definitions than the young adult subjects. These findings suggest that AD individuals have difficulty in integrating semantic features when interpreting novel noun-noun expressions and that both AD and healthy elderly individuals have morphosyntactic impairments related to the identification of the modifying and head nouns of noun-noun expressions.     

Semantic versus phonological false recognition in aging and Alzheimer's disease

Patients with Alzheimer's disease (AD) have been found to exhibit lower levels of false recognition of semantic associates compared with healthy older adults. Because these patients may show impaired performance of episodic and semantic memory tasks, this finding could be explained by deficits in episodic memory, semantic memory, or both. The authors adapted a paradigm for comparison of semantic versus phonological false recognition. They found that: (a) patients with AD exhibited lower levels of corrected false recognition of semantic, phonological, and hybrid (mixed semantic and phonological) lists than older adults, and (b) patients with AD showed very similar levels of false recognition for all list types. These results suggest that only episodic memory deficits are necessary to explain the lower level of false recognition of semantic associates observed in patients with AD when compared to older adults. Additionally, (c) older adults showed greater levels of semantic, phonological, and hybrid false recognition than younger adults, extending previous false recognition research of semantically related words and categorized colored photographs to phonologically related words.     

Education and children with Down syndrome: neuroscience, development, and intervention

Of the recent advances in education-related research in Down syndrome, the characterization of the Down syndrome behavioral phenotype has become a potentially critical tool for shaping education and intervention in this population. This article briefly reviews the literature on brain-behavior connections in Down syndrome and identifies aspects of the Down syndrome behavioral phenotype that are potentially relevant to educators. Potential challenges to etiologically informed educational planning are discussed.     

The development of route learning in Down syndrome,Williams syndrome and typical development: investigations with virtual environments

The ability to navigate new environments has a significant impact on the daily life and independence of people with learning difficulties. The aims of this study were to investigate the development of route learning in Down syndrome (N = 50), Williams syndrome (N = 19), and typically developing children between 5 and 11 years old (N = 108); to investigate use of landmarks; and to relate cognitive functions to route‐learning ability in these groups. Overall, measures of attention and long‐term memory were strongly associated with route learning, even once non‐verbal ability was controlled for. All of the groups, including 5‐ to 6‐year‐old TD children, demonstrated the ability to make use of all landmark types to aid route learning; those near junctions, those further from junctions, and also distant landmarks (e.g. church spire, radio mast). Individuals with WS performed better than a matched subset of TD children on more difficult routes; we suggest that this is supported by relatively strong visual feature recognition in the disorder. Participants with DS who had relatively high levels of non‐verbal ability performed at a similar level to TD participants.     

The relationships between television viewing in midlife and the development of Alzheimer's disease in a case-control study

The relationship between leisure activities and development of cognitive impairment in aging has been the subject of recent research. We examined television viewing in association with risk of developing Alzheimer's disease (AD) in a case-control study. Given recent focus on the importance of intellectually stimulating activities as preventive measures against cognitive decline, it is important to examine the effects of less stimulating but common activities. Data are from 135 Alzheimer's disease cases and 331 healthy controls. Demographic characteristics and life history questionnaire responses on the number of hours spent on 26 leisure activities during middle-adulthood (ages 40-59) were analyzed. Logistic regression was used to examine the effects of middle-adulthood leisure activities on case vs. control status. Results indicate that for each additional daily hour of middle-adulthood television viewing the associated risk of AD development, controlling for year of birth, gender, income, and education, increased 1.3 times. Participation in intellectually stimulating activities and social activities reduced the associated risk of developing AD. Findings are consistent with the view that participation in non-intellectually stimulating activities is associated with increased risk of developing AD, and suggest television viewing may be a marker of reduced participation in intellectually stimulating activities.     

Imitation and representational development in young children with Down syndrome

Competence in object search and pretend play are argued to reflect young children's representational abilities and appear delayed in children with Down syndrome relative to social and imitative skills. This paper explores the effects on object search and play of this social strength in children with Down syndrome. Three experiments compared performance on traditional tasks with modified tasks designed to assess the role of imitation in object search and pretend play. Children with Down syndrome, relative to typically‐developing children, were able and willing to imitate hiding actions when no object was hidden (Experiment 1). When imitation was prevented in object search, children with Down syndrome searched less effectively than typically‐developing children (Experiment 2). In play, children with Down syndrome expressed more willingness to imitate a counter‐functional action, modelled by the experimenter, despite apparent competence in spontaneous functional play (Experiment 3). These findings indicate that object search and play behaviours of children with Down syndrome rely more heavily on imitation than is the case for typically‐developing children. The implications for the development of children with Down syndrome and models of representational development are discussed.     

Speech monitoring skills in Alzheimer's disease, Parkinson's disease, and normal aging.

We examined the abilities of 15 patients with dementia of the Alzheimer type (DAT), 22 patients with Parkinson's Disease (PD), and 141 healthy subjects (ranging in age from 30 to 79 years) to detect and correct their own speech errors. Each subject was shown the Cookie Theft picture of the BDAE (Goodglass & Kaplan, 1972. The assessment of aphasia and related disorders. Philadelphia: Lea & Febiger.) and instructed to tell the examiner the "...story of what's happening in the picture." Self-monitoring performance was assessed by tabulating the number of uncorrected errors as well as repaired errors. We divided repairs into two types based on the psycholinguistics literature (van Wijk & Kempen, 1987. Cognitive Psychology, 19, 403-440). Speech corrections were judged to be lemma repairs when the reparandum was a single word, and reformulation repairs when a new syntactic constituent was added to the reparandum. Patients with DAT corrected only 24% of their total errors and patients with PD only 25%. Healthy subjects, by contrast, corrected from 72 to 92% of their total errors. Patients with DAT tended to rely on reformulation repairs while patients with PD used both repair types about equally often. While healthy elderly Ss (in the 70s group) utilized lemma repairs more often than the reformulation strategy, all other healthy Ss used both strategies about equally often. Across all groups naming performance correlated negatively with numbers of undetected errors. Results point to a previously unrecognized communication disorder associated with PD and DAT and manifested by an impairment in the ability to correct output errors. This impairment may be related to attentional and frontal dysfunction in the two patient groups.     

Different patterns of cognitive slowing produced by Alzheimer's disease and normal aging

Aging has previously been shown to produce a generalized proportional slowing of all cognitive operations. In contrast, the present results suggested that Alzheimer's disease produces a disproportionate reduction in the speed with which patients carry out one or more mental operations. The tasks that demented patients found particularly difficult involved either a self-directed search of their lexicon or the use of familiarity information.     

Down syndrome: cognitive phenotype

Down syndrome is the most prevalent cause of intellectual impairment associated with a genetic anomaly, in this case, trisomy of chromosome 21. It affects both physical and cognitive development and produces a characteristic phenotype, although affected individuals vary considerably with respect to severity of specific impairments. Studies focusing on the cognitive characteristics of Down syndrome were reviewed, and while performance in most areas could be predicted based upon overall intellectual disability, relative weaknesses were consistently found to be associated with expressive language, syntactic/morphosyntactic processing, and verbal working memory. This profile of uneven deficits could result from a failure to develop typically automatic processing for speech perception and production, and this possibility is discussed along with its implications for intervention.     

Alzheimer's disease: progress in the development of anti-amyloid disease-modifying therapies

The amyloid hypothesis--the leading mechanistic theory of Alzheimer's disease--states that an imbalance in production or clearance of amyloid beta (Abeta) results in accumulation of Abeta and triggers a cascade of events leading to neurodegeneration and dementia. The number of persons with Alzheimer's disease is expected to triple by mid-century. If steps are not taken to delay the onset or slow the progression of Alzheimer's disease, the economic and personal tolls will be immense. Different classes of potentially disease-modifying treatments that interrupt early pathological events (ie, decreasing production or aggregation of Abeta or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective Abeta42-lowering agents; statins; anti-Abeta aggregation agents; peroxisome proliferator-activated receptor-gamma agonists; and others. Safety and serious adverse events have been a concern with immunotherapy and gamma-secretase inhibitors, though both continue in clinical trials. Anti-amyloid disease-modifying drugs that seem promising and have reached phase III clinical trials include those that selectively target Abeta42 production (eg, tarenflurbil), enhance the activity of alpha-secretase (eg, statins), and block Abeta aggregation (eg, transiposate).