Cognitive assessment using the Rapid Assessment for Developmental Disabilities, Second Edition (RADD-2).

BACKGROUND: Individuals with developmental disabilities (DD) often have severe impairments and maladaptive behaviours that make it difficult to reliably assess their cognitive abilities. Given these challenges, the Rapid Assessment of Developmental Disabilities, Second Edition (RADD-2), was designed to measure general cognitive ability in this population. The purpose of this study is to demonstrate the battery's psychometric properties when used with individuals with DD who have challenging behavioural and psychiatric conditions and for those who have limited verbal skills. METHOD: The cognitive and adaptive behaviour skills of 193 children and adults with DD and considerable medical, behavioural and/or psychiatric problems were evaluated using the first and second editions of the RADD, Kaufmann Brief Intelligence Test - 2nd Edition, and Scales of Independent Behaviour - Revised Edition. Medication side effects and challenging behaviours were assessed using the Aberrant Behaviour Checklist. RESULTS: There were no floor or ceiling effects on the RADD-2. Both the nonverbal index and total scores had strong concurrent validity with other abbreviated tests of intellectual ability and good discriminant validity from measures of adaptive behaviour and medication side effects. RADD-2 scores also had strong criterion validity as they successfully differentiated between all levels of intellectual functioning. Age and sex did not differentially affect RADD-2 performance, and the co-occurrence of psychiatric conditions did not negatively affect performance. The only medical condition associated with lower RADD-2 performance was epilepsy. CONCLUSIONS: The RADD-2 can quantify the differential cognitive abilities of individuals with DD, even for those with minimal communication skills, challenging behaviours or severe medication side effects that can typically complicate assessment. This brief cognitive battery can be used to measure changes due to interventions, on the one hand, and progression of neurological disease, on the other.

Rapid assessment of cognitive function in down syndrome across intellectual level and dementia status.

BACKGROUND: Adults with Down syndrome (DS) are at risk of developing dementia and cognitive assessment is a fundamental part of the diagnostic process. Previously, we developed a Rapid Assessment for Developmental Disabilities (RADD), a brief, broadly focused direct test of cognition. In the current report, we assess whether the RADD is sensitive to dementia in DS and the degree to which it compares with other cognitive measures of dementia in this population. METHODS: In a sample of 114 individuals with DS, with dementia diagnosed in 62%, the RADD was compared with the Dementia Questionnaire for Mentally Retarded Persons (DMR), the Bristol Activities of Daily Living Scale, Severe Impairment Battery (SIB), and the Brief Praxis Test (BPT). RESULTS: The RADD showed predicted effects across intellectual disability (ID) levels and dementia status (p < 0.001). Six-month test-retest reliability for the subset of individuals without dementia was high (r(41) = 0.95, p < 0.001). Criterion-referenced validity was demonstrated by correlations between RADD scores and ID levels based upon prior intelligence testing and clinical diagnoses (rs (114) = 0.67, p = 0.001) and with other measures of cognitive skills, such as the BPT, SIB, and DMR-Sum of Cognitive scores (range 0.84 through 0.92). Using receiver operating characteristic curves for groups varying in pre-morbid severity of ID, the RADD exhibited high sensitivity (0.87) and specificity (0.81) in discriminating among individuals with and without dementia, although sensitivity was somewhat lower (0.73) for the subsample of dementia cases diagnosed no more than 2 years prior to their RADD assessment. CONCLUSION: Taken together, findings indicated that the RADD, a relatively brief, easy-to-administer test for cognitive function assessment across ID levels and dementia status, would be a useful component of cognitive assessments for adults with DS, including assessments explicitly focused on dementia.

The relationship between living arrangement and adherence to antiepileptic medications among individuals with developmental disabilities.

BACKGROUND: Non-adherence to antiepileptic drugs (AEDs) is associated with considerable morbidity and mortality in the general population but little is known about adherence in individuals with intellectual disability (ID). METHOD: Using the records of a closed pharmacy billing system over a 30 month period, we examined the medication non-adherence rates for AEDs among 793 individuals with ID. We calculated the medication possession ratio (number of days each participant was in possession of an AED), and defined non-adherence as 25% or more of the exposure days without the possession of an AED. All participants studied had filled prescriptions for AEDs spanning at least 6 months. RESULTS: Controlling for age and gender, we found non-adherence rates varied by living arrangement. Compared with those living in group homes, individuals with ID living in family homes or in semi-independent settings were significantly less adherent to AEDs (P < 0.0003). CONCLUSION: Non-adherence to AEDs is a potential medical risk for individuals with ID that is significantly impacted by the type of community living arrangement.

Neuroimaging of individuals with Down's syndrome at-risk for dementia: evidence for possible compensatory events.

BACKGROUND: We report functional and structural brain indicators that may precede the onset of dementia in individuals with Down's syndrome (DS). METHODS: Middle-aged adults with DS (n=19), a group known to be at high risk for dementia, were studied with (1) positron emission tomography (PET) to determine cerebral glucose metabolic rate (GMR), (2) structural magnetic resonance imaging (MRI) to determine gray matter volume (GM), and (3) ratings of potential dementia indicators based on a structured interview of caregiver observations designed to evaluate individuals with low intelligence. RESULTS: Although none of the participants showed clinical signs of dementia, ratings of dementia indicators were correlated to both functional and structural imaging. The strongest correlations (p<.05, corrected for multiple comparisons) included the combination of higher GMR and decreased GM volume in parts of the temporal cortex, including the parahippocampus/hippocampus, in the thalamus, caudate, and frontal lobe (BA 47). INTERPRETATION: The combination of increased GMR overlapping with less gray matter in these areas may be consistent with a compensatory brain response to an early stage of the disease process.

Possible compensatory events in adult Down syndrome brain prior to the development of Alzheimer disease neuropathology: targets for nonpharmacological intervention.

Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology progressively with age but clinical signs of dementia are delayed by at least 10 years after the first signs of disease. Some individuals with DS do not develop dementia despite extensive AD neuropathology. Given the discordance between clinical decline and AD neuropathology, compensatory events may be of particular relevance for this group. Imaging studies using PET suggest compensatory increases in metabolic rate in vulnerable brain regions in DS prior to the development of dementia. Neurobiological studies of similarly aged DS autopsy cases provide further evidence of activation of plasticity mechanisms. Genes that are overexpressed in DS (APP, DSCAM, MNB/DYRK1A, and RCAN1) produce proteins critical for neuron and synapse growth, development and maintenance. We present the hypothesis that these genes may lead to developmental cognitive deficits but paradoxically with aging, may participate in molecular cascades supporting neuronal compensation. Enhancing or supporting compensatory mechanisms in aging individuals with DS may be beneficial as suggested by intervention studies in animal models. In combination, adults with DS may be a unique group of individuals well-suited for studies involving the manipulation or upregulation of compensatory responses as an approach to promote successful brain aging in the general population.

Rapid assessment of severe cognitive impairment in individuals with developmental disabilities.

BACKGROUND: Most standardized intelligence tests require more than 1 hour for administration, which is problematic when evaluating individuals with intellectual disabilities and developmental disabilities (IDDD), because a significant proportion of these individuals can not tolerate lengthy evaluations. Furthermore, most standardized intelligence tests are of limited usefulness for individuals with severe cognitive deficits because of floor effects. METHODS: A number of low-difficulty items were selected from standardized tests. A total of 271 participants with profound, severe, moderate and mild levels of cognitive impairment took part in this study. In the formative phase, 68 participants were evaluated with the selected items, and those items that differentiated between levels of cognitive impairment were retained in the battery. The instrument was then modified and standardized with an additional 203 participants. RESULTS: The instrument, referred to as the Rapid Assessment for Developmental Disabilities (RADD), required 10-25 min for administration. Internal reliability estimates from the RADD total score and from individual subtests satisfied conventional and rigorous statistical criteria (median alpha r = 0.93). The RADD total score was strongly correlated with the level of cognitive impairment (rho = 0.86). The RADD total score and individual subtests differentiated between all levels of cognitive impairment ( Wilks Lambda = 0.135, F(42,525.832) = 12.075, P < 0.001). Receiver operating characteristic curves indicated the instrument was particularly sensitive to the cognitive abilities of the most seriously impaired participants. CONCLUSIONS: The RADD, composed of low-difficulty items from published tests, is rapidly administered, assesses a wide range of cognitive skills and differentiates among all levels of cognitive impairment. The battery has clinical utility with populations exhibiting short attention spans because of its ability to quickly assess a wide range of cognitive abilities. The RADD also has research potential for the documentation of cognitive function in studies of individuals with IDDD.

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain.

Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alpha-secretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Abeta) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Abeta degradation and clearance.

Longitudinal prescribing patterns for psychoactive medications in community-based individuals with developmental disabilities: utilization of pharmacy records.

BACKGROUND: Little is known about longitudinal prescribing practices for psychoactive medications for individuals with intellectual disabilities and developmental disabilities (IDDD) who are living in community settings. METHODS: Computerized pharmacy records were accessed for 2344 community-based individuals with IDDD for whom a total of 3421 prescriptions were written during a 17-month period of study. Forty-two psychoactive medications were rank ordered in terms of prescription frequency. RESULTS: Fifty-two per cent (52%) of all prescriptions written during the study period were for psychoactive medications. Anticonvulsant, antipsychotic and antidepressant medications were the most commonly filled prescriptions among psychoactive medications. Sixty per cent (62%) of the study population was given prescriptions for more than one psychoactive medication and 36% received three or more psychoactive medications. During the study period there was a statistically significant increase in prescriptions filled for olanzapine, risperidone, valproic acid, and clonazepam whereas prescriptions filled for thioridazine, haloperidol, and benzotropine showed a significant decline (P < 0.05-0.001). Distribution of psychoactive drug class by age showed that the majority of prescriptions were filled for individuals between 20 and 50 years with the exception of prescriptions for psychostimulants which peaked for individuals prior to 20 years. CONCLUSIONS: (1) Analysis of pharmacy billing records provides a method for assessing prescribing patterns of psychoactive medications in community-based individuals with IDDD. (2) Polypharmacy for psychoactive medications is prevalent in this setting. (3) The second-generation antipsychotic medications are prominently represented by an increasing number of filled prescriptions during the study period.

Temporal cortex hypermetabolism in Down syndrome prior to the onset of dementia.

BACKGROUND: Adults with Down syndrome (DS) are at increased risk for dementia and provide an opportunity to identify patterns of brain activity that may precede dementia. Studies of early Alzheimer's disease (AD) and risk of AD show decreased function in posterior cingulate and temporal cortex as initial indicators of the disease process, but whether the origin and sequence of predementia brain changes are the same in DS is unknown. METHODS: The regional cerebral glucose metabolic rates (GMR) among middle-aged nondemented people with DS (n = 17), people with moderate AD (n = 10), and age-matched control subjects (n = 24) were compared using PET during a cognitive task. RESULTS: Statistical parametric mapping conjunction analyses showed that 1) both DS and AD groups had lower GMR than their respective controls primarily in posterior cingulate and 2) compared with respective controls, the subjects with DS had higher GMR in the same areas of inferior temporal/entorhinal cortex where the AD subjects had lower GMR. The same results were replicated after 1 year of follow-up. CONCLUSIONS: As the DS subjects were not clinically demented, inferior temporal/entorhinal cortex hypermetabolism may reflect a compensatory response early in disease progression. Compensatory responses may subsequently fail, leading to neurodegenerative processes that the authors anticipate will be detectable in vivo as future GMR decreases in inferior temporal/entorhinal cortex are accompanied by clinical signs of dementia.

Parallel compensatory and pathological events associated with tau pathology in middle aged individuals with Down syndrome.

Aged individuals with Down syndrome (DS) develop senile plaques and neurofibrillary tangles consistent with Alzheimer disease (AD). Prior to or in parallel with AD pathology, compensatory growth responses may occur. Immunohistochemistry and confocal microscopy studies in the hippocampus from 15 individuals ranging in age from 5 months to 67 years compared markers of normal and abnormal tau accumulation (phosphorylated tau [AT8, MC-1], tau-1, N-terminal tau) with the extent and location of neuronal growth marker immunoreactivity (BDNF, GAP-43, MAP-2). In middle age (30-40 years), prior to entorhinal neuron loss, the earliest tau accumulation occurred in the outer molecular layer (OML), which was consistent with both pathological and compensatory fetal tau expression. These events were followed at a later age, associated with entorhinal neuron loss, by an increase in GAP-43. Hilar neurons exhibiting a sprouting morphology were also noted. Age-dependent observations in the DS brain in the current study parallel hippocampal compensatory responses described in entorhinal cortex lesion studies in rodents. Thus, compensatory growth responses may occur in DS prior to extensive AD pathology and may be one mechanism underlying observations in PET studies of hypermetabolism in the entorhinal cortex of individuals with DS.

Beta-amyloid deposition and neurofibrillary tangle association with caspase activation in Down syndrome.

Individuals with Down syndrome (DS) and Alzheimer's disease (AD) develop senile plaques, neurofibrillary tangles (NFT), and neuron loss. Recent studies demonstrate the activation of apoptotic pathways in AD; less data is available in DS. The DS brain was examined using immunocytochemistry and antibodies against the active fragment of caspase-8 (AC, 8) and to caspase-3 cleavage products of fodrin (CCP), a neuronal cytoskeleton protein. The hippocampus demonstrated widespread accumulation of fodrin CCP and AC8 in NFTs and dystrophic neurites. Individual neurons contained intracellular beta-amyloid (Abeta) and fodrin CCP providing evidence that caspase activation can occur with both NFT and Abeta. Abeta within or around neurons in addition to contributing to NFT formation may also trigger apoptotic pathways. Caspase activation may lead to the cleavage of critical cellular proteins and neuronal cell death associated with DS.

Oxidation of Abeta and plaque biogenesis in Alzheimer's disease and Down syndrome.

The processes involved with beta-amyloid (Abeta) degradation and clearance in human brain are not well understood. We hypothesized that the distribution of oxidatively modified Abeta, as determined by an affinity-purified antibody in the entorhinal and frontal cortices of Alzheimer's disease (AD), Down syndrome (DS), nondemented elderly control cases, and canine brain, would provide insight into the mechanisms of Abeta accumulation. Based upon plaque counts, oxidized Abeta was present within 46-48% of diffuse and primitive plaques and 98% of cored plaques. Dense punctate deposits of oxidized Abeta were distributed throughout the neuropil in AD and DS brains but were also present within controls with mild neuropathology and isolated cognitive impairments. Confocal studies indicate that punctate oxidized Abeta deposits were within activated microglia. Oxidatively modified Abeta may reflect the efforts of microglial cells to take up and degrade Abeta. Oxidative modification of Abeta may be an early event in Abeta pathogenesis and may be important for plaque biogenesis.

Neurological changes and emotional functioning in adults with Down Syndrome.

This study was designed to examine emotional changes in adults with Down Syndrome (DS) over time and whether changes in these psychological variables were associated with brain atrophy on MRI scan and the presence of pathological reflexes on the neurological examination. Participants were 26 adults with DS and their caregivers. Caregivers completed a measure of emotional functioning about individuals with DS at two different time points (1 year apart). Levels of cognitive functioning were measured and neurological and MRI examinations were performed on all subjects at initial testing. Significant group effect separated those with and without pathological findings on MRI and neurological exam across three different scales: depression, indifference, and pragmatic language functioning. Problems of poor pragmatic language functioning appeared later in the course of suspected Alzheimer's disease (AD), as demonstrated by a significant group effect at time 2, but not at initial testing. In these subjects, the primary emotional change was a decline in social discourse (e.g. conversational style, literal understanding, verbal expression in social contexts). These emotional levels were stable over time, regardless of degree of cognitive decline. Specific emotional changes occur during the course of AD which were associated with abnormal findings from MRI and from neurological examination. These results, along with abnormalities in brain imaging and the presence of pathological reflexes, suggested that frontal lobe dysfunction is likely to be an early manifestation of Alzheimer's Disease in Down Syndrome.

Down syndrome and Alzheimer's disease: a link between development and aging.

A subset of aged individuals with Down syndrome (DS) exhibits the clinical features of Alzheimer's disease (AD) but our ability to detect dementia in this population is hampered by developmental differences as well as the sensitivity of existing test tools. Despite the apparent clinical heterogeneity in aged individuals with DS, age-associated neuropathology is a consistent feature. This is due to the fact that trisomy 21 leads to a dose-dependent increase in the production of the amyloid precursor protein and subsequently the production of the amyloidogenic fragments leading to early and predominant senile plaque formation. A review of the existing literature indicates that oxidative damage and neuroinflammation may interact to accelerate the disease process particularly in individuals with DS over the age of 40 years. By combining clinical information with measures of brain-region specific neuropathology we can "work backwards" and identify the earliest and most sensitive clinical change that may signal the onset of AD. For the past 50 years, investigators in the fields of mental retardation, developmental disabilities, and aging have been interested in the curious link between AD and DS. The morphologic and biochemical origins of AD are seen in the early years of the lifespan for individuals with DS. Study of the process by which AD evolves in DS affords an opportunity to understand an important link between development and aging. This review will focus on advances in the molecular and clinical basis of this association.

Complement association with neurons and beta-amyloid deposition in the brains of aged individuals with Down Syndrome.

To study the link between beta-amyloid (Abeta) and neuroinflammation, we examined the levels of complement as a function of age and extent of Abeta deposition in Down Syndrome (DS) brain. C1q, the first component of the complement cascade, was visualized using immunohistochemistry in the frontal, entorhinal cortex, and hippocampus of 12 DS ranging from 31 to 69 years of age. C1q was consistently associated with thioflavine-S positive Abeta plaques in DS brain and increased with more extensive age-dependent Abeta deposition. In contrast, little or no C1q labeling was associated with diffuse or thioflavine-S negative Abeta deposits. Neurons in the hippocampus and entorhinal cortex, but less frequently in frontal cortex, were C1q positive in DS cases with sufficient neuropathology to have a diagnosis of Alzheimer's disease. C1q-positive neurons were associated with activated microglia. These results provide evidence for Abeta-mediated inflammatory factors contributing to the rapid accumulation of neuropathology in DS brain.

Molecular dating of senile plaques in the brains of individuals with Down syndrome and in aged dogs.

beta-Amyloid (Abeta) is a constituent of senile plaques found with increasing age in individuals with Down syndrome (DS) and in the canine model of aging. Sections of DS and dog brain were immunostained using an affinity-purified polyclonal antibody for a posttranslationally modified Abeta with a racemized aspartate at position 7 (d7C16). The immunostaining characteristics of d7C16 Abeta in DS and dog brain indicate that it is present in all plaque subtypes, including the thioflavin-S-negative diffuse plaques that develop with age in dogs. The youngest DS case exhibited weak immunolabeling for d7C16 but the extent of d7C16-positive plaques increased with age. In addition, d7C16-positive plaques were initially found in clusters in the superficial layers of the frontal and entorhinal cortex but, with advancing age, increasing numbers appeared in deeper layers, suggesting a progression of Abeta deposition from superficial to deeper cortical layers. Ultrastructural studies in DS brain were confirmed using perfused dog brain and provided consistent results; thioflavin-S-negative diffuse plaques consist of fibrillar Abeta and racemized Abeta is associated with thicker and more highly interwoven fibrils than nonracemized Abeta. The use of antibodies to modified forms of the Abeta protein should provide insight into the progression of plaque pathology in DS and Alzheimer's disease brain.

Delayed-onset profound biotinidase deficiency.

Children with biotinidase deficiency usually exhibit symptoms at several months to years of age. We describe four children who had symptoms later in childhood or during adolescence; they had motor limb weakness, spastic paresis, and eye problems, such as loss of visual acuity and scotomata, rather than the more characteristic symptoms observed in young untreated children with the disorder. These older children each have different mutations, but they are the same as those of children who have exhibited symptoms at an early age. Biotinidase deficiency should be considered in older children who suddenly experience limb weakness and/or spastic paresis and eye symptoms.

Premature aging in persons with Down syndrome: MR findings.

PURPOSE: To determine whether persons with Down syndrome have features of premature aging on routine MR imaging sequences. METHODS: Sixty MR studies (in 30 persons with Down syndrome and 30 age- and sex-matched control subjects) were reviewed retrospectively by two blinded examiners. Sagittal T1-weighted and axial T2-weighted spin-echo images were evaluated for the presence and severity of three markers of brain aging: atrophy, white matter lesions, and T2 hypointensity of the basal ganglia, referenced to the examiner's internal standard of normal for that age and sex. RESULTS: Persons with Down syndrome had higher prevalence and severity of the three markers studied than the control subjects. Atrophy and white matter lesions increased in prevalence with age; abnormal T2 hypointensity of the basal ganglia was more equally distributed with age. CONCLUSION: Persons with Down syndrome have features of premature aging detectable at routine MR imaging.

Magnetic resonance imaging of the aging brain in Down syndrome.

MRI studies to date have confirmed and expanded upon findings of morphologic differences between the brains of subjects with DS and those of the general population found by CT and post-mortem examination. [table; see text] Hippocam pal and neocortical structures are smaller in DS while unexpectedly the parahippocampal gyrus was found to be larger. MRI has demonstrated that subjects with DS develop signs associated with [table; see text] brain aging at an earlier age. These findings include increased rate of dilatation of ventricles, increased peripheral atrophy, and increased deep white matter lesions. In addition, changes that are associated with AD occur earlier in the DS population. Functional studies reveal decreasing cerebral perfusion with age in adults with DS, a pattern similar to non-DS subjects with clinically progressive dementia, and provide evidence for altered blood-brain barrier permeability. Dynamic MRI studies have also shown adults with DS to have fluctuating cortical CSF volumes, similar to some elderly non-DS subjects and subjects with shunted hydrocephalus. This is a new finding in brain aging that suggests a relationship between aging in DS and edematous states of the brain.

Cortical CSF volume fluctuations by MRI in brain aging, dementia and hydrocephalus.

Dynamic MR imaging has revealed dramatic fluctuations in the appearance of CSF in the cortical sulci and cortical subarachnoid spaces in aging individuals and patients with hydrocephalus, dementia and Down syndrome in contrast to young healthy volunteers. The changes have been interpreted as volume fluctuations that represent undamped CSF hydrodynamics and have implications with respect to the origin of CSF in the cortical regions and with respect to the similarity between aging and dementia and edematous states of the brain.