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.

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.

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.

Plasticity of hippocampal circuitry in Alzheimer's disease.

Two markers of neuronal plasticity were used to compare the response of the human central nervous system to neuronal loss resulting from Alzheimer's disease with the response of rats to a similar neuronal loss induced by lesions. In rats that had received lesions of the entorhinal cortex, axon sprouting of commissural and associational fibers into the denervated molecular layer of the dentate gyrus was paralleled by a spread in the distribution of tritiated kainic acid-binding sites. A similar expansion of kainic acid receptor distribution was observed in hippocampal samples obtained postmortem from patients with Alzheimer's disease. An enhancement of acetylcholinesterase activity in the dentate gyrus molecular layer, indicative of septal afferent sprouting, was also observed in those patients with a minimal loss of cholinergic neurons. These results are evidence that the central nervous system is capable of a plastic response in Alzheimer's disease. Adaptive growth responses occur along with the degenerative events.

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.

Pancytopenia in mannosidosis.

A case of autoimmune pancytopenia is described in a patient with mannosidosis who developed anti-platelet and anti-neutrophil antibodies and a low haptoglobin level. Bone marrow biopsy and 111InCl3 bone marrow scanning demonstrated hypoplasia of the marrow with a paucity of "storage cells." Pathogenic mechanisms and implications for other inborn errors of metabolism are discussed.

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.

The cellular pathology of neuronal ceroid-lipofuscinosis. A golgi-electronmicroscopic study.

A cerebral biopsy specimen from a 4-year-old girl with a moderately advanced stage of the late infantile form of neuronal ceroid-lipofuscinosis was observed in routine cell and fiber stains and in Golgi and electronmicroscopic preparations. There was no evidence of neuronal degeneration or loss. Golgi impregnations identified a fusiform enlargement of proximal axon segments of most pyramidal neurons and some polymorphic neurons but not of other cortical neuronal classes. Typical curvilinear inclusions were found in all cells and appeared to be impacted within the dilated proximal axon segments of pyramidal neurons. The numbers of type II synapses on the axon hillock and dilated proximal axon segments of pyramidal neurons were much reduced, whereas type I synapses remained abundant in the neuropil.

Communicating hydrocephalus and lysosomal inclusions in mannosidosis.

A 32-year-old man with mannosidosis had a gait disorder develop that was associated with communicating hydrocephalus. The gait disorder improved with ventriculoperitoneal shunting, but proximal muscle weakness remained. Biopsy specimens of muscle and nerve disclosed typical lysosomal inclusions in both tissues, as well as selective loss of unmyelinated axons.

Mannosidosis. New clinical presentation, enzyme studied, and carbohydrate analysis.

Mannosidosis is a rare inborn error of metabolism characterized by deficiency of the lysosomal enzyme alpha-mannosidase and widespread storage of complex carbohydrate, which is enriched in mannose. Two affected unrelated males, aged 6 and 26 years, are reported. Both had a nonprogressive encephalopathy with moderately severe mental retardation. The older patient showed several unique features, including massive gingival hyperplasia associated with histiocytes containing large amounts of a material with the staining characteristics of glycoprotein. The best determinant of mannose storage proved to be the ratio of mannose to other carbohydrates in urinary polysaccharides. The enzyme deficiency in this disease is most convincingly demonstrated at pH values below 4.0. The ability of zinc to activate the mutant enzyme in vitro offers a possible mode of therapy for this disease. Retarded individuals with a Hurler-like appearance and gum hyperplasia of unknown cause should be screened for alpha-mannosidase deficiency.

Serum and urinary trisaccharides in mannosidosis.

A trisaccharide, Man2glcNAc, was the most abundant urinary oligosaccharide (161-558 mumol per liter) in a patient with mannosidosis. By means of a newly developed high-performance liquid chromatography (HPLC) procedure, we were able to measure low levels of serum trisaccharide (0.1--0.4 nmol per milliliter). This is the first report of the measurements of serum oligosaccharides in mannosidosis. Our observations on the disparate relationship between serum and urinary concentrations of this trisaccharide suggest that a facilitated renal clearance of oligosaccharides may be related to the nonprogressive aspect of this disorder.

Familial amentia, unusual ventricular calcifications, and increased cerebrospinal fluid protein.

A sibship originally reported by Friedman and Roy as showing severe mental retardation, strabismus, hyperactive tendon reflexes, lalling speech, and foot deformities was restudied. Three major additional findings were noted. The cerebrospinal fluid protein concentration was increased two to three times above normal in four siblings who were available for study. Radiographs of cranial structures in three siblings showed identical pathologic intracranial calcifications which correspond in distribution to the choroid plexus. The choroid plexus was not demonstrable in one patient when radiolabeled 99m-Tc-pertechnetate was injected without perchlorate. Neuropathologic findings in one sibling included small subcortical heterotopias and atrophy of the choroid plexus with encasement by glial fibrils. These findings denote a new heredofamilial neurologic syndrome associated with mental retardation and a disorder of choroid plexus.

Vitamin B6-dependent seizures: pathology and chemical findings in brain.

A 13 1/2-year-old child died with vitamin B6-dependent seizures in progress. Microscopic findings in brain included an abnormally sparse quantity of central myelinated fibers in the cerebral hemispheres. Glutamic acid concentrations were elevated and GABA concentrations reduced in the frontal and occipital cortices but not in the spinal cord. All other amino acid concentrations were normal, except for increased cystathionine in the occipital cortex. Pyridoxal-5-phosphate (PLP) was reduced in the frontal cortex. Glutamic acid decarboxylase activity comparable to that of controls was detected when the PLP concentration was greater than 0.05 mM. These findings suggest that pyridoxine-dependent seizures in man are associated with reduced GABA concentrations in the brain and with diminished central white matter structures.

The cellular pathology of Menkes steely hair syndrome.

The principal neuropathologic abnormality observed in three autopsy cases of Menkes steely hair syndrome was widespread nerve cell loss and gliosis, especially severe in the cerebral and cerebellar cortex and in the relay nuclei of the thalamus. Granular stellate cells of neocortical layer IV and the granule cells of the cerebellum are cell classes which were particularly severely depopulated. The degree of reduction of myelinated axons is consistent with axonal degeneration secondary to nerve cell loss. There are also prominent abnormalities in the patterns of dendritic arborization of surviving cortical pyramids and cerebellar Purkinje cells as seen in Golgi impregnations. The deviant neuronal forms are probably due, in part, to failure of innervation by afferent fiber systems during the fetal as well as postnatal epochs.

A light and electron microscopic study of mannosidosis.

The present work investigated the light and electron microscopic changes in hypertrophied gingiva in a patient with mannosidosis. The biopsy specimens studied covered a period of 20 months; biopsy specimens were taken before and after a therapeutic trial with oral and local zinc sulfate. The intensity of the disease was progressive, in spite of the zinc, and was characterized by marked hyperplasia of the epithelium and severe inflammation of the stroma. Many of the cells in the inflammatory infiltrate, as well as cells indigenous to the gingiva, showed a striking vacuolation of their cytoplasm. Histiocytes were most numerous and also were most heavily vacuolated, but fibroblasts, endothelial cells, plasma cells, and epithelial cells also manifested the vacuolar change. In the histiocytes, the vacuoles occupied most of the cytoplasm, ranged widely in size, and were contiguous, molded, and intercommunicating. The vacuoles were bound by a single membrane and were filled predominantly by a finely granular material of medium density but also by varying amounts of coarser, darker granules, fragmented membranes, myelin-like figures, lipid droplets, and small vesicles. The vacuoles were interpreted as being consistent with secondary lysosomes that contained excessively stored substrate, similar to what has been observed in the mucopolysaccharidoses, in which the vacuoles have also been demonstrated histochemically and cytochemically to contain acid phosphatase, a known lysosomal marker.

Down's syndrome, aging, and Alzheimer's disease: a clinical review.

This review has been directed towards those aspects of DS which bear upon pathological aging. Clinical dementia in DS has heretofore been studied largely by retrospective methods with variable findings. A prospective study utilizing techniques designed to measure cognitive performance in a poorly verbal, retarded population is badly needed. There is definitive evidence for Alzheimer's disease changes in the brains of DS patients with some suggestion of altered topography compared to the general population. Immunological studies have established a T-cell deficiency in DS that may be linked to precocious aging of thymic-dependent processes. Both antiviral and nonantiviral effects of interferon are accentuated in cell culture systems utilizing DS tissue, presumably as a consequence of the localization of the interferon gene(s) on chromosome 21. Multiple endocrine studies confirm the high frequency of autoimmune disease, an abnormality that may be related to the problems of immune surveillance in DS. Precocious aging has been noted in regards to measures of skin elasticity, fenestration of cardiac valves, and premature cataracts. The 21st chromosome has been implicated in the elevated activity of superoxide dismutase, a finding of significance in regard to potential intracellular damage from increased levels of peroxide. Several studies have suggested a compensatory increase in glutathione peroxidase.

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.

Density and distribution of NMDA receptors in the human hippocampus in Alzheimer's disease.

We examined the distribution and density of N-methyl-D-aspartate (NMDA) displaceable L-[3H]glutamate binding sites in human hippocampal samples obtained postmortem from Alzheimer's disease (AD) patients and from age-matched controls. Binding to NMDA receptors was stable for at least 72 h postmortem, and the pharmacological profile corresponded to that described using electrophysiology. NMDA receptors were concentrated in the terminal fields of major hippocampal pathways including the perforant path, Schaffer collaterals and the hippocampal output to the subiculum, all of which are proposed to use an excitatory amino acid transmitter. Little if any change in hippocampal receptor density was observed in AD patients compared to age-matched controls except in one case where major hippocampal cell loss occurred. The distribution of NMDA receptors did, however, correspond to the predilection for neuritic plaques and neurofibrillary tangles in hippocampal subfields.

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.

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.