Aging With Down Syndrome: The Dual Diagnosis: Alzheimer’s Disease and Down Syndrome

Abstract

Background:

People with Down syndrome (DS) enjoy a longer life expectancy now than they ever have before and are therefore at greater risk of developing conditions associated with aging, including dementia.

Objectives:

To explore the phenomenon of dementia in DS.

Methods:

Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published until 2017. Search terms included Alzheimer’s disease, cognitive impairment, dementia, DS, and trisomy 21. Publications found through this indexed search were reviewed for further references.

Results and Conclusions:

Virtually, all subject aged 35 to 40 show key neuropathologic changes characteristic of Alzheimer’s disease, but only a part of them show clinical signs of dementia, usually around the age of 50 years. Early signs of dementia in people with DS may be different from those experienced by the general population. Failure to recognize this can delay diagnosis and subsequent interventions.

Introduction

Down syndrome (DS) or trisomy 21 (Ts21) is a model of all human disorders that are the result of supernumerary copies of a genomic region. It is the most common form of chromosomal abnormality affecting many tissues both during development and later on in adult life and leading to intellectual disability –ID- (defined as “a significantly reduced ability to understand new or complex information and to learn and apply new skills”), ¹ with a prevalence rate of 1 of every 650 to 1000 live births. ^{2 –4} During the prenatal period, DS pregnancies are associated with an elevated rate of spontaneous loss. ⁵ Increased risk of a birth of an infant with DS is directly related to maternal but not paternal age. ⁶ A 20-year-old woman has a 1 in 1500 chance of having a child with DS; a 45-year-old woman has a 1 in 50 chance or greater. From 1979 through 2003, the birth prevalence of DS rose from 9.0 to 11.8 (31.1%) per 10 000 live births in 10 representative US regions; this increase, largely due to women conceiving after age 35, portends an ever-growing population of people with DS who may be subject to pathogenic aging. ⁷ A study by de Graaf et al ⁸ estimated the prevalence of DS as 13.1 per 10 000 in Ireland, 7.7 per 10 000 in the Netherlands, and 6.1 per 10 000 in England/Wales. The syndrome affects 5.8 million people worldwide. ⁹ Males with DS are almost always infertile, but there are numerous accounts of successful pregnancies in females. ¹⁰ The complex pathobiology of DS results in physical deficits and biochemical changes that can lead to multiple comorbid conditions. In addition to the features that are found in everyone with the disorder, there are many DS-associated phenotypes that have variable penetrance and severity, and this is likely the complex result in part of genetic and epigenetic variation, environmental factors, and stochastic events. Although the phenotypical features of patients with DS are variable, there are enough similar symptoms to enable the expert to suspect the diagnosis. Individuals with DS typically are microcephalic and have characteristic facies, hypotonia, and small stature. The degree of mental impairment varies ranging from mild to moderate. Children often have cardiac and gastrointestinal congenital malformations, various types of leukemia, growth retardation, immune disorders, and other clinical pathologies. ¹¹ Similar to adults in the general population, adults with ID, both with and without DS, have benefited from advances in medical care, nutritional practices, and public health policies that occurred during the 20th century, resulting in a dramatic extension of their life expectancy. ^12-13 Early reports on DS suggested that survival was very limited, and in the United Kingdom, life expectancy was estimated to be just 9 years of age in 1929. ¹⁴ The life expectancy for individuals with DS has increased dramatically in recent decades; a recent study estimated that the average life expectancy of individuals with DS is 60 years. ¹⁵ With this increase in life expectancy, in addition to the congenital ID, subjects with DS older than 40 years show an age-related cognitive impairment. ¹⁶ Zigman et al ¹⁷ found that individuals with DS older than the age of 50 were significantly more likely to have dementia than individuals with ID due to other causes, with odds ratios ranging from 1.68 to 8.56. Coppus et al ¹⁸ studied 506 people with DS, aged 45 years and earlier. The overall prevalence of dementia was 16.8%. Up to the age of 60, the prevalence of dementia doubled with each 5-year interval. Up to the age of 49, the prevalence was 8.9%, from 50 to 54 it is 17.7%, and from 55 to 59 it is 32.1%. In the age category of 60 and above, there is a small decrease in prevalence of dementia to 25.6%, probably due to the higher mortality rates among individuals with dementia. However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of cognitive impairments.

Historical Notes

Despite the condition not officially being recognized until the 19th century, cases of Ts21 have existed throughout human history. Walker and colleagues ¹⁹ published an abstract on 7200-year-old skeletal remains from Santa Rosa Island, which were found in a Native American cemetery. The researchers noted that several of these skeletal characteristics are consistent with those found in DS; however, given the lack of a representative skeletal collection of individuals with DS, this diagnosis was not conclusive. Depiction of DS may come from Olmec figurines. The Olmecs were a tribe that flourished in the Gulf of Mexico region between 1500 before Christ and 300 Anno Domini. Numerous artifacts made of a variety of materials have survived, with manifest facial and other bodily appearances, including deformities. Two authors felt that some of the artifacts showed such “striking similarities” to DS, particularly with regard to facial and cranial characteristics. They assumed that the artifacts concerned were the representation of individuals with the syndrome. ²⁰ In 1866, the Victorian physician John Langdon Down published his now famous article, “Observations on an ethnic classification of idiots,” in the London Hospital Reports. ²¹ In that essay, he attempted to classify patients with mental retardation by comparing them to 5 ethnic groups. He used the term “mongoloid” to describe the condition, due to his opinion, that children with DS shared similar physical features to people from the Blumenbach Mongolian race. Although Down “Mongolian idiot” and “mongoloid” labels would be viewed as racist today, the use of these terms was a consequence of the prevailing ideas of racial hierarchies from his era. ²² Down felt that “mongolism” could be attributed to tuberculosis of the parents, thus causing a developmental arrest at an earlier stage of creation. ²³ It was not until 1959 that Professor Jerome Lejeune in France and Patricia Jacobs and colleagues in United Kingdom independently proved that DS was caused by the triplication of the 21st chromosome. ^24-25 Prior to 1956, we did not know the exact number of chromosomes in the typical human cell. The association between Mongoloid “imbeciles” and the national group of Mongols was increasingly challenged through the first half of the 20th century, but the designation “Mongolism” continued in use in major scientific journals into the 1970s. In 1961, the Editor of the Lancet issued his ruling: “We urge that the expressions which imply a racial aspect of the condition be no longer used. The signers of this letter are inclined to replace the term “mongolism” by such designations as “Langdon-Down anomaly” or “Down’s syndrome” (p. 775). ²⁶ The redesignation of the condition was confirmed by the World Health Organization in 1965. The People’s Republic of Mongolia had approached the Director General and said that they objected to the use of the descriptive term “Mongolian Idiot” as it was derogatory to them. ²⁷ Today, we know that DS is found in all ethnic backgrounds and socioeconomic statuses. It is important to remember people with DS and other intellectual and developmental disabilities were a key target in the eugenics movements. Through Aktion-T4 program (a program of involuntary euthanasia in Nazi Germany), Hitler murdered an estimated 200 000 people with intellectual and developmental disabilities, a large number being people with DS. ²⁸ Prejudice and discrimination against individuals with DS continue today. ²⁹

Chromosome 21 and DS

Chromosome 21 (HSA21) is the smallest human autosome. It represents around 1% to 1.5% of the human genome. Considerable progress has been made toward discovering the gene content of HSA21, now estimated to be 329, but the functions of most of these genes and their specific contributions to the final DS phenotype still remain unknown. Down syndrome results of a chromosomal aberration that arises during fertilization and causes an extra chromosome to be present in the pair 21. The embryological etiology of DS is mainly correlated with the nondisjunction of an HSA21. The Ts21 karyotype is present in 93% to 95% of people with DS; a further 3% to 4% exhibit translocation anomalies (extra chromosome 21 material is attached to another chromosome), and 1% to 3% are mosaic (only some of the cells have an extra chromosome). ¹⁰ About 86% of the extra chromosomes are maternally derived, mainly due to nondisjunction in meiosis, and approximately 9% of full Ts21 is due to paternal meiotic error, less than 5% of full Ts21 is caused by mitotic errors. ³⁰ The exact mechanism for this meiotic error remains unknown. According to the size of the triplicated genomic region, trisomies can be divided into 4 categories: complete, or whole-chromosome, trisomies; partial trisomies; microtrisomies; and triplication of single genes or single functional genomic elements. ³¹ Reports have identified a region of HSA21 known as DS critical region (DSCR; a region at the end of the long arm of HSA21) in which the expression of some genes would modulate the main clinical characteristics of this pathology, ^{32 –34} but there has been much debate about the existence of selected, critical regions or genes on Hsa21 as the main one responsible for ID or for the other symptoms. However, evidence suggests that genes outside this region may also contribute to the DS phenotype. ³⁵ Recently, it has been suggested by Pelleri and colleagues ³⁶ that the “DSCR does not cover the role so far attributed to it and it has been suggested a different small region, on 21q22.13, as critical to the phenotype…A highly restricted DSCR (HR-DSCR) of only 34 kb on distal 21q22.13 has been identified as the minimal region whose duplication is shared by all DS subjects and is absent in all non-DS subjects” (p. 1).

The complete DS phenotype is presumed to develop from the increased activity of the overexpressed HSA21 genes’ products. Among the sequences present on HSA21, the gene encoding amyloid precursor protein (APP), a transmembrane glycoprotein, is thought to have a key role in the pathology of Alzheimer’s disease (AD). The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. ³⁷ The widely accepted AD model posits that amyloid accelerates downstream neurodegeneration, which is the underlying substrate of cognitive impairment. Overproduction of Aβ invariably leads to the early development of AD-like pathology in DS. The link between triplication of the APP gene and subsequent overproduction of Aβ leading to AD dementia in DS is further supported by the fact that partial trisomy of HSA21 that does not result in the presence of an extra APP does not lead to dementia or any AD pathology. ³⁸

Neuroanatomical Changes

Despite the apparent clinical heterogeneity in aged individuals with DS, age-associated AD neuropathology is a consistent feature. Brain morphology in DS at birth is primarily normal, but postnatal development slows. Until recently, our understanding of the structural brain abnormalities in DS was almost exclusively based on autopsy studies; improvements in magnetic resonance imaging (MRI) and image-processing techniques allowed quantitative explorations of brain structure in living subjects with DS. ³⁹ Postmortem investigations of DS brains have yielded a number of neuropathologic findings, the most prominent of which are reduced gross brain weight, frontal and temporal lobe hypoplasia, cortical gyral atrophy, cerebral ventriculomegaly, small brain stem, and hypoplasia of the cerebellum, especially of its “middle lobe.” ⁴⁰ In contrast, subcortical structures, such as the lenticular nuclei and the posterior parietal and occipital cortical gray matter, have relatively normal brain volumes. ⁴¹ Hippocampus volume is disproportionally reduced, whereas amygdala volume reductions do not exceed the overall reduction in brain size. Mullins and colleagues, ⁴² using MRI in 192 adults, compared the volume of whole brain in DS subjects with and without dementia. Individuals with dementia showed significant reductions in the volume of the whole brain, hippocampus, and temporal lobes and a significant elevation in the volume of the lateral ventricle, compared to their nondemented counterparts. Similar to patients with sporadic AD, people with DS, who have died when 40 years or older, irrespective of dementia, show cerebral atrophy, accumulation of Aβ deposits in extracellular senile plaques (SPs) and perivascular amyloid (amyloid angiopathy), intraneuronal neurofibrillary tangles (NFTs), and extracellular neuritic plaques. ⁴³ Ever since the first description of presenile dementia by Alzheimer in 1906, SPs and NFTs have been regarded as the “signature” pathological lesions of AD. ⁴⁴ Significant amyloid binding with positron emission tomography is found before any signs of cognitive or functional decline in DS. ⁴⁵ A target of early Aβ pathology in DS is the entorhinal cortex later spreading to the hippocampus and involving neocortical association regions in more advanced stages of the disease. ⁴⁶ The Aβ pathology begins to accumulate in childhood (as young as 8 years). ³⁷ In many individuals with DS, the rate of Aβ deposition increases markedly between 35 and 45 years and becomes associated with NFTs. In AD-DS, there are more and earlier plaques and tangles in the hippocampus compared to early-onset AD and late-onset AD in non-DS. ³⁷ Functional brain imaging has shown an increased glucose metabolic rate in inferior temporal/entorhinal cortex compared to age-matched controls, ⁴⁷ suggesting that a compensatory response may be occurring in the medial temporal lobes. ⁴⁸

Clinical Features of AD-DS

A loss of cognitive function in middle-aged adults with DS was reported as early as 1876, soon after the identification of the syndrome, ⁴⁹ more than 30 years before Alois Alzheimer described the neuropathological–neuropsychiatric entity that now bears his name, ⁵⁰ and more than 70 years before the association of AD with DS was published. ⁵¹ The prevalence of dementia increases with age rising from approximately 15% after age 45 years to approximately 75% after age 65 years, although there is large variation between individuals. ^18,52 For example, place of residence was significantly associated with dementia: Prevalence rates have varied from 4% in a community sample ⁵³ to 88% in an institution-based sample. ⁵⁴ This difference was accounted for by the fact that those clients in residential care were significantly older than their community counterparts. ⁵² The clinical features are those of dementia in the general population, but differences in presentation may occur due to the effects of the underlying level of intellectual function or where the underlying ID leads to a delay in diagnosis. ⁵⁵ It has been argued that, in the case of people with DS, the exact hierarchy of loss of cognitive function is very difficult to establish. ⁵⁶ Some authors ^57-58 affirmed that in patients with AD-DS, as is the case in sporadic AD, loss of immediate memory is among the most prominent symptoms of the disease, but that it is difficult to detect this in the former group because of “floor effect” (ie, when a test is considered too difficult and all the participants score too low) obtained with standard tests. Recently, Lautarescu et al ⁵⁹ evaluated the published literature on longitudinal data in order to identify the cognitive and behavioral changes occurring during the prodromal and early stages of AD-DS. They analyzed 15 peer-reviewed articles included a total number of 831 participants. Nine suggested that “frontal-like symptoms” were the earliest sign of AD-DS in this population. Only 2 studies reported memory as the earliest sign of dementia. Two studies reported no decline that could not be accounted for by normal aging and 2 did not report the order in which domains of cognitive functioning were affected. As an explanation for “frontal signs first” hypothesis, Azizeh et al suggested that the sequence of brain regions affected by Alzheimer’s dementia may differ with earlier amyloid deposition in the frontal lobes in the Down population, whereas in the general population, the hippocampus (and thus episodic memory) would be affected first. ⁶⁰ Disinhibition and apathy, as well as executive dysfunction, seem to be omnipresent in the prodromal phase, whereas reports are still too divergent to assume that this is also true for depression. ⁶¹ Temple and Konstantareas ⁶² compared the behavioral and emotional changes accompanying AD in individuals with DS and individuals with AD only. The authors found that persons with AD-DS have less severe psychotic behaviors, fewer hallucinations, and fewer delusions and were more likely to engage in physical movements than those with AD only. Cooper and Prasher ⁶³ reported that among learning disabled adults with dementia, those with DS showed a higher prevalence of maladaptive behaviors, such as depressed mood, restlessness, disturbed sleep, and being excessively uncooperative than those with learning disability of other etiologies. These cognitive disorders often result in markedly compromised functional skills, including basic activities of self-care such as feeding and bathing. ⁶⁴ A longitudinal study in the United States showed severely diminished verbal long-term storage and retrieval processing abilities in those with early-stage dementia compared to those without a diagnosis of dementia. ⁶⁵ Misrecognition or socially deficient communication may be an early sign of frontal lobe dysfunction in DS and may represent a striking change from previous well-developed social capacities in the disorder. ⁶⁶ According to Roizen and Patterson, ¹² clinical signs and symptoms of AD in adults with DS are noted in 75% of individuals older than 60 years of age and are most frequently seizures (58%), change in personality (46%), focal neurological signs (46%), apathy (36%), and loss of conversational skills (36%). The lack of identification of apathetic behavior might cause caregivers to misinterpret the symptoms as deliberate opposition or laziness. Gait dyspraxia is characterized by diminished capacity to correctly use the legs for ambulation when this deficit cannot be attributed to sensory impairment, motor weakness, poor coordination, or other identifiable causes. Gait deterioration without other consistent neurologic signs was described as a common early finding in the series of patients with DS. ⁶⁷ The association of disorders of gait with the development of dementia over time suggests that the mechanisms underlying gait change and cognitive change may be closely related. ⁶⁸ The prevalence of epilepsy increases with age, reaching 46% in those older than 50. With regard to the onset of seizures, a bimodal distribution is noted: 40% of patients begin having seizures before the age of 1 year, and another 40% start with seizure activity in the third decade of life. The younger group outnumber primarily infantile spasms and tonic–clonic seizures with myoclonus and in the older partial simplex or complex seizures as well as tonic–clonic seizures. ⁶⁹ Late-onset myoclonic epilepsy in DS is characterized by myoclonic jerks on awakening, generalized tonic–clonic seizures, and generalized spike and wave on EEG; an interesting observation is that AD and progressive myoclonic epilepsy are both linked to chromosome 21. ⁷⁰ The association of generalized epilepsy with elderly DS represents an epiphenomenon in evolution which is associated with a progressive deterioration in cognitive and motor functions. Persons with DS and dementia have more health comorbidities than those without, ⁷¹ especially lung disease, gastrointestinal disorders, visual and hearing impairments, and often lose weight. ⁷¹ Cosgrave et al ⁵⁶ and Visser et al ⁷² have described subjects with end-stage dementia. All were unresponsive to their environment and lost the ability to speak. They were totally dependent and unable to walk, all were incontinent, and almost all had seizures, and many had Parkinsonian features. In conclusion, according to our opinion, often, small changes in person’s usual activities of daily life indicate the possible onset of dementia. Furthermore, symptoms that should alert about the onset of AD-DS are behavioral changes such as reduced empathy, social withdrawal, emotional instability, and apathy.

Differential Diagnosis

The diagnosis of dementia in people with DS can be confounded by baseline variability in cognitive functioning, comorbid medical conditions, and differences in diagnostic approaches. ⁷³ The physician may attribute symptoms to DS instead of to a new disease process because of the difficulty in obtaining a good history in light of limited expressive speech and a tendency to manifest medical problems as behavior problems. ⁷⁴ Dementia needs to be differentiated from somatic conditions that occur frequently in individuals with DS, for example, depression and hypothyroidism.

Depression

Depression giving rise to secondary cognitive impairment must be well recognized, as it can have a very strong influence on how people with DS perform on neuropsychological tests and in turn complicate the possible diagnosis of dementia. Both biological and psychosocial risk factors influence the development of depression. The reported prevalence rates of the disorder in DS range from 0% to 11.1%. ⁷⁵ However, identifying depression in people with intellectual disability presents problems due to difficulties with self-report of symptoms, diminished communication skills, and differences in presentation of psychopathology. The most frequent symptom of depression in DS is a loss of interest (95.4%); other highly prevalent symptoms are sleeping disorders and decreased appetite or weight loss (both in 81.8%), agitation (72%), anxiety (40.9%), fatigue (36.3%), and memory deficits (22.7%). ⁷⁶ Decline in adaptive skills (eg, dressing, washing, feeding) is significantly associated with depression.

Hypothyroidism

Adequate thyroid function is essential for normal development and retention of cognitive function throughout life. Both congenital hypothyroidism and acquired hypothyroidism are common in patients with DS, with an estimated community prevalence varying from 9% to 35%. ^{77 –79} Low thyroid function at any age causes cognition to deteriorate because hypothyroidism prevents the brain from adequately sustaining the energy (glucose)-consuming processes needed for neurotransmission, memory, and other higher brain functions. Also, subclinical hypothyroidism may be a predisposing factor for cognitive impairment (subclinical hypothyroidism is defined as an elevated TSH level in the presence of normal circulating T4 and T3 concentrations plus the absence of features of clinical hypothyroidism). Even in the setting of normal thyroid function, thyroid antibody levels should be measured, and the diagnosis of Hashimoto encephalopathy considered in patients with DS who present with rapid cognitive decline. ⁸⁰

Obstructive sleep apnoea/hypopnoea syndrome

Adults with DS frequently have obstructive sleep apnea/hypopnea syndrome (OSAHS), with obstructive apnea, hypoxemia, hypoventilation, and sleep fragmentation. ⁸¹ Obstructive sleep apnea/hypopnea syndrome is a disorder characterized by repetitive cycles of airway obstruction, resulting in pauses in breathing, sleep fragmentation, and intermittent hypoxia, which can in turn lead to diurnal symptoms such as sleepiness and mood impairment. It has been known for some time that neurocognitive deficits occur with a high frequency in OSAHS. These deficits can affect any cognitive domain, including learning, memory, and attention. ⁸² It has long been recognized that untreated OSAHS leads to cognitive impairment, and, given that adults with DS are already cognitively impaired by virtue of their ID, the impact of OSAHS in this population may be even more pronounced. ⁸³

Assessment

There are inherent difficulties in diagnosing cognitive decline in those with a preexisting cognitive impairment. Furthermore, based on the level of ID, individuals may have significant associated communication difficulties making an accurate diagnosis challenging. Despite the neuropathological connection between Alzheimer’s dementia and DS, the diagnosis of Alzheimer’s in people with DS is far from an easy task. The presentation of dementia in people with ID may be subtle and may go unrecognized. The diagnosis of dementia remains clinically integrative based on history, physical examination, and cognitive assessment. Given the heterogeneity of premorbid intelligent quotient and functional independence, the approach to determine cognitive decline is to ascertain a change in decline from the baseline level of function and performance of daily skills. The evaluation of the functional status in subjects with ID and dementia is crucial both in the diagnostic and in postdiagnostic phase. The large interindividual variability in cognitive and functional abilities characteristic of populations with ID throughout their lives makes the very concept of “normal” functioning inapplicable. Loss of adaptive function may be the first sign of dementia and may be associated with slowing down in the workshop or the decrease in self-care skills in the home domain. The assessment should be conducted with support from an individual very familiar with the patient. In the absence of a personal historian who can accurately and comprehensively attest to an individual’s baseline level of functioning, the assessment of a reported or observed change may be exponentially more complicated. ⁸⁴ Often, individuals with ID are cared for by numerous persons throughout their lifetime, and often newly involved caregivers will presume that their current level of ability represents their baseline level of functioning and, thus, miss signs of early decline. ⁸⁴ As in diagnosing anyone with possible dementia, it is vital to rule out any other physical conditions or other possible explanations. A large variety of physical illnesses and sensory impairments (especially hearing) are especially common in the population with DS and should be considered when attempting to assess cognitive and behavioral change. A full medical evaluation including a comprehensive physical examination and visual assessments should be performed on each individual. Because middle ear problems and associated hearing loss are common among individuals with DS, routine screenings in these areas are recommended. Conditions particularly common in DS should be explored most thoroughly (eg, depression, folic acid abnormalities in patients on anticonvulsants, cognitive deterioration secondary to medications, eg, anticholinergic medication). The vast majority of instruments used for the detection of dementia were developed from studies of individuals with normal intellectual development, being intended for application in the general population. Many of the diagnostic tools used for the general population may not consider the intellectual skills and status of individuals with DS and may present an inaccurate representation of the situation. The screening instruments commonly used in the general population such as the Mini-Mental State Examination (MMSE) ⁸⁵ cannot be used in this population because of possible floor effect. There is no “MMSE” or equivalent screening instrument which is widely used by all practitioners. Individual screening instruments may not produce the most accurate results when screening for cognitive impairment in DS and have compared poorly to clinical judgment, which alone was found to be superior to a range of different tests. ⁸⁶ To differentiate between pathological and normative aging, it is essential to know what normative aging is and how the abilities of an individual compare to those of others with similar education, age, and premorbid abilities. The absence of a “gold standard” for the diagnosis of dementia in people with ID makes it difficult to establish the cutoff scores required for the diagnosis of dementia. Although the physician’s clinical judgement has regularly been regarded as the “gold standard” against which other measures are tested, some authors have argued that this could result in a higher number of adults being diagnosed. ⁸⁶ Furthermore, many of the assessments used have “floor effects,” and assessments used to diagnose dementia in the general population are not sensitive-enough for individuals with a learning disability, and significant adaptations are needed. Difficulties with diagnosis are in large part due to the intraindividual variability in performance in people with DS over cognitive tasks. ⁸⁷ Inclusion of at least 1 standardized tool for cognitive assessment is recommended because it generates a score that can be tracked over time and provides an additional rigid data point that can be repeated on subsequent encounters. ⁸⁴ The ideal test and outcome measure to use in neuropsychological research depends upon the cognitive ability of interest, the specific research question, and population assessed, in addition to floor/ceiling effects and the spread of results observed. ⁸⁸ Some instruments have been developed and validated for the diagnosis of dementia in this population, including the Dementia Scale for Down’s Syndrome, ⁸⁹ the Dementia Questionnaire for People With Learning Disabilities, ^90-91 the Cambridge Examination for Mental Disorders of Older People With Down’s Syndrome, ⁹² the Down’s Syndrome Mental State Examination, ⁹³ and the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities. ⁹⁴ Combined assessment using observer-rated questionnaires and direct neuropsychological testing may provide the highest sensitivity and specificity. ⁹⁵ Observer-rated scales must, however, be interpreted with caution, as aging caregivers may be developing cognitive difficulties themselves or may know the subject too well or insufficiently to be objective. ⁷³ Sheehan and colleagues ⁹⁶ conceived a research to investigate the validity and reliability of a clinical diagnosis of dementia (defined as confirmed diagnosis of dementia recorded by clinicians following clinical assessment) in people with DS and to compare it with the performance of established criteria (International Statistical Classification of Diseases and Related Health Problems 10th Revision [ICD-10] ⁹⁷ and Diagnostic and Statistical Manual, Fourth Edition-Text Revision [DSM-IV-TR]). ⁹⁸ The study showed that when making a diagnosis of dementia in people with DS, clinicians who are experienced in assessing this population for cognitive decline are able to make accurate diagnoses at a relatively early stage of the disease. Clinical diagnoses were more inclusive than using ICD-10 or DSM-IV-TR criteria, suggesting that clinicians relied on dementia symptoms that are specific to this population.

Management

Managing the health needs of people with DS and dementia will require a multiagency and multidisciplinary approach, with different professionals being needed at different stages of the dementia. ⁹⁹ Although there are approved treatments for AD, which have been assessed in those with DS, there is little established methodology for preventing or treating cognitive loss in DS or in reducing incipient dementia. Furthermore, the intellectual disability associated with DS, as well as inadequacies in living arrangements, may be predisposing factors for poor medication adherence. ¹⁰⁰ At this time, the treatments available for adults with DS and dementia are mainly supportive. Rivastigmine, galantamine, memantine, and donepezil have been used to treat DS-associated dementia. Donepezil and galantamine are selective inhibitors of acetylcholinesterase (AChE), while rivastigmine is a dual inhibitor of AChE and butyrylcholinesterase. Memantine is a noncompetitive antagonist of NMDA. Elevated frequencies of adverse effects from donepezil have been reported in subjects with AD-DS. ¹⁰¹ Clinicians should be aware of the more serious side effects, for example, reduced heart rate (which can be significant in an individual with DS who may already have a low resting heart rate), stomach ulcer with bleeding, seizures, and depression: starting at a low dose, and slower titration of dosage can reduce the frequency of side effects, particularly in an aging population. ¹⁰² A review identified no randomized controlled trials of galantamine in people with DS. ¹⁰³ Well-designed, adequately powered studies are required for rivastigmine. ¹⁰⁴ Despite promising indications, memantine is not an effective treatment. ¹⁰⁵ To determine whether vitamin E would slow the progression of cognitive deterioration, a randomized, double-blind controlled clinical trial was conducted. ¹⁰⁶ The study provides evidence that the antioxidant vitamin E did not slow the progression of cognitive deterioration in DS. In recent years, there has been growing interest in nonpharmacological interventions for people with dementia, starting from the increasing evidence for the role of individual features (ie, age and education level), environmental stimuli (eg, engagement in familiar, professional, and leisure activities), lifestyle factors (ie, physical exercise and balanced diet), expertise, and experience as protective agents against dementia development. ¹⁰⁷ Activities and communication strategies may need to be modified to take into account the person’s deteriorating memory and thinking skills. There is a clear lack of studies addressing the efficacy of nonpharmacological interventions in patients with AD-DS. Eating problems and dietary changes have been reported in patients with dementia, and weight loss and undernutrition are common complications that occur. ¹⁰⁸ Some simple practices should be employed to address a decreased appetite: These include preparing favorite foods, increasing physical activity, or planning for several small meals rather than 3 large ones per day. ¹⁰⁹ As people reach the end of their life, palliative care teams will need to be engaged to support the people and their carers and staff to ensure that they have a “good death.” ¹¹⁰

Possible Effects of Disclosing a “New” Diagnosis to Patients With DS and Their Caregivers

Goffman ¹¹¹ describes stigma as the public’s attitude toward a person who possesses an attribute that fails to meet societal expectations and who is consequently perceived as “deeply discredit[ed] within a particular social interaction.” Stigmatization is characterized by chronic social and physical avoidance of a person(s) by other people. Despite these negative consequences, empirical research, in the area of ID stigma, is limited and atheoretical. ¹¹² On the contrary, there is a body of work in anthropology and sociology on dementia that is relevant to consideration of the relationship of stigma and dementia. ¹¹³ People with dementia and other mental disorders have psychological, behavioral, and social consequences of the diagnosis being often thought to be incompetent, dangerous, and unpredictable. ¹¹⁴ An individual who possesses good insight and awareness into his or her deficits is able to verbalize the nature, the severity, and the consequences that the deficits can have on himself or herself and others: The extent of this awareness has been associated with the patient’s psychological response to receiving a dementia diagnosis. ¹¹⁵ A study from the United Kingdom investigated the relationship between awareness of having an intellectual disability and stigma: Cunningham and Glenn ¹¹⁶ interviewed 77 people with DS and their parents. They found that only half of their participants were aware of having DS or a disability. People with DS may not be informed or aware of a diagnosis of dementia. This does not prevent them from experiencing the disease or holding beliefs about what is happening to them. ¹¹⁷ Only a published research ¹¹⁷ has been conducted in the area of subjective experience of people with DS and dementia, and further attention is required to this area. Carers should be encouraged to find strategies or be offered help to manage their emotions related to loss of the individual’s abilities, to support one another, to see behaviors as part of dementia instead of failings of the individual, and to work on employing their own coping mechanisms. ¹⁰⁹ It is assumed by many carers that their adult child with DS syndrome will move into supported accommodation; however, as Watchman stated “accommodation for people with learning disabilities is not traditionally designed for the changing and complex needs of people with dementia and vice versa. ¹¹⁸ Referrals are often made to services for older people with dementia even though the person with DS may only be in their forties or fifties” (p. 82). ¹¹⁸

Conclusions

Adults with DS are known to be at high risk of developing dementia relatively early in life. The course of dementia in people with DS may differ from that in the general population. Early signs of dementia in people with DS may be different from those experienced by the general population, and a failure to recognize this can lead to a delay in diagnosis and subsequent interventions. It is important to emphasize that it is not only cognitive decline which is important in the diagnosis of dementia in the population with DS but that behavioral and emotional symptoms must also be taken into account. Difficulties with diagnosis are in large part due to the intraindividual variability in performance in people with DS over cognitive tasks. Given the complexities in diagnosing dementia in people with DS, many attempts have been made to standardize the assessment process, but there is unfortunately no gold standard by which to diagnose Alzheimer’s dementia in this population. Early intervention helps determine optimal care and enhances awareness in carers and family members. The issues of origin, pathogenesis, and the natural history of dementia in DS awaits further prospective studies. Further research investigating the value of diagnostic instruments and rating scales, outcome post-illness, and response to treatment is required.