An improved method for detecting telomere size differences in T-lymphocyte interphases from older people with Down syndrome with and without mild cognitive impairment.

Telomere size (quantified by fluorescence intensity and physical lengths) in short-term T-lymphocyte cultures from adults with Down syndrome (DS) with and without mild cognitive impairment (MCI-DS) or dementia was compared. For these studies, dementia status was determined based on longitudinal assessments employing a battery of cognitive and functional assessments developed to distinguish adult-onset impairment from preexisting developmental disability. In the course of our studies using a MetaSystems Image Analyzer in combination with ISIS software and a Zeiss Axioskop 2, we found that Fluorescein isothiocyanate (FITC) telomere fluorescence referenced to chromosome 2-identified FITC probe fluorescence as a nontelomere standard (telomere/cen2 ratio) showed great promise as a biomarker of early decline associated with Alzheimer's disease (AD) in this high-risk population. We have now obtained a cen (2) CY3 probe that can clearly be distinguished from the blue-green FITC interphase telomere probe, providing a clear distinction between telomere and centromere fluorescence in both interphase and metaphase. We used FITC/CY3 light intensity ratios to compare telomere length in interphases in adults with DS with and without MCI-DS or dementia. Five age-matched female and five age-matched male pairs (n = 10) all showed clear evidence of telomere shortening associated with clinical progression of AD (P < 0.002 - P < 0.000001), with distributions of mean values for cases and controls showing no overlap. We also examined the time needed for microscopy using interphase versus metaphase fluorescence preparations. With interphase preparations, examination time was reduced by an order of magnitude compared with metaphase preparations, indicating that the methods employed herein have considerable practical promise for translation into broad diagnostic practice.

Dementia of the Alzheimer's type and accelerated aging in Down syndrome.

This case study, of a woman with Down syndrome and dementia of the Alzheimer's type (DAT), follows the course of her decline over an 11-year period until death at age 57. Detailed neuropathological findings are also presented. This case illustrates features of premature aging that are typically associated with Down syndrome, and the progressive changes in memory and cognition that are usually associated with DAT. Although the subject's cardiovascular condition and thyroid disorder were treated, they may have contributed to the decline of her memory. This case shows the difficulty in diagnosing dementia in an individual with mental retardation who suffered comorbid episodes of depression and psychosis.

Fragile X expression in short-term whole blood cultures is affected by cell density.

The effect of cell density on expression of the fragile site at (X)(q27.3) in short-term whole-blood cultures from patients with fragile X [fra(X)] or Martin-Bell syndrome was studied. A significant increase in fra(X) frequency was observed in 7 of 8 samples when cell density was decreased. Higher fra(X) frequency was not always noted at below-routine density, but in some cases fra(X) expression was depressed at above-routine density. We conclude that decay of the FUdR effect explains the fact that fra(X) expression is affected by culture density. It is significant that a relationship exists between the two; it suggests that in order to maximize fra(X) expression in cases with low-percentage fra(X) with standard methods, cell density may have to be adjusted. It is possible that in individuals who are normally nonexpressing, such as some obligate female carriers and nonpenetrant males, fra(X) expression may be sensitive to cell density effects.

Mouse chromosome fragility.

When cultures of fibroblast-like cells from inbred mouse strains RBC/Dn and AEJ/GnRk were exposed to 5-fluorodeoxyuridine (FUdR), non-random strain-specific distributions of chromosome gaps, breaks and exchanges were observed. Throughout the genomes there appeared to be specific sites at which lesions occurred preferentially. Two strain-specific fragile sites were identified in strain RBC/Dn at G-band 15A2, and at G-band 19B in strain AEJ/GnRk. Constitutive fragile sites at G-bands 12A2 and 18A2 were identified in both strains. A strain-specific marker at G-band 9B was found in strain AEJ/GnRk. The fragile sites reported here provide an animal model for the study of chromosome fragility as well as polymorphic markers for linkage studies.

Fragile X chromosome frequency is consistent temporally and within replicate cultures.

Fragile X frequencies differ widely between different fra(X)-positive individuals. The basis for this variation is unknown, but may reflect genetic differences or unknown environmental factors. To determine more fully the individual and familial variation in fra(X) frequencies, we studied 15 individuals. The present study showed that fra(X) frequency, with few exceptions, was consistent for the same individual both over time and within replicate cultures. This confirms previous observations by others on the consistency of fra(X) expression by others, and indicates the extent of expected variability within replicate cultures. Consideration of this variability should enable improved fra(X) identification.

Are whole words perceptual units in reading?

Two experiments examined the perceptual processing of letters embedded within one- or two-syllable words and visually similar nonwords. Two-choice speeded discrimination tasks were used in which subjects were informed of both the identity and location of critical display information before stimulus presentation. Exp. 1 results indicated that one-syllable words differing by two letters were more quickly discriminated than one-syllable words differing in a single letter. Such performance gains due to the presence of redundant information suggest that one-syllable words form compelling perceptual units. In contrast, similar nonword pairs differing by two letters were discriminated no faster than two nonwords differing in a single letter. This latter pattern of results also was found for two-syllable words and similar nonwords, suggesting that neither unfamiliar nonwords nor two-syllable words form compelling perceptual units. In Exp. 2 subjects were given substantial practice on a task that forced attention to multiple letters within the stimulus displays. Results replicated the findings of Exp. 1, except that performance for both one-syllable words and matched nonwords now showed improved performance in the presence of redundant information. Taken together results of the two experiments suggest that: (a) the size of compelling perceptual units seems limited, with entire words sometimes functioning as multiunit patterns and (b) unit size is not necessarily related to the correspondence between letter order and pronounceability.

Visual perseveration in normal and mentally retarded children.

Visual perseveration was investigated within mentally retarded and second, fifth, and eighth grade normal children (Ns = 12 each group). Subjects matched an auditorially presented click to the onset and offset of visually presented stimuli. Time differences between visual stimulus offset and the point at which subjects reported simultaneity of the click and visual stimulus offset was assumed to reflect visual perseveration. Results showed: (a) no differences between the normal children as a function of age; (b) no difference between groups for stimuli of 100 msec. or longer duration; and (c) retarded subjects judged stimuli of 20 and 50 msec. to be of shorter duration than did normal subjects. This highly specific distinction between retarded and normal subjects suggests a difference in an early stage of perceptual processing.

Comments on "Encoding and high-speed memory scanning..." by Maisto and Jerome.

Maisto and Jerome (1977) reported differences in reaction-time (RT) performance between retarded and nonretarded adolescents. They used the additive factor method, and their results showed differences in the speed of active memory scanning between the two populations; however, they violated a critical assumption underlying interpretation of the results, as there was nonindependence of the slope and intercept values of the function relating memory load to RT of retarded subjects. This departure from theoretically acceptable conditions makes the Maisto and Jerome data difficult to interpret.

The perception of identity in simultaneously presented complex visual displays.

Two experiments were conducted in order to examine the information processing in a visual matching task, using digit sequences of varying complexity as the stimuli. Traditionally, reaction times for "same" judgments do not fit into a single-process self-terminating feature testing model, while those for "different" judgments do. Bamber (1969) proposed a two-stage model to account for the data, and the results of these experiments support this type of model. Strong evidence implying that Bamber's "identity reporter" has a limited capacity in terms of stimulus complexity was also found. This complexity seems to be deemed by stimulus discriminability and the number of "chunks" of information rather than by "bits" of information being transmitted (Miller, 1956).

Speech dysfluency and manual specialization in Down's syndrome.

The relationship between speech dysfluency and manual lateralization was studied in 31 adults with Down's syndrome. Analysis of speech samples from videotapes indicated that frequency of dysfluency ranged from normal to very severe; 42% of the subjects were stutterers. Manual lateralization was measured by the demonstrated use of five objects (pencil, comb, toothbrush, ball and scissors); 61% of the subjects had a clear right-hand preference, 13% a left-hand preference, and the remaining subjects (39%) were mixed-handed. Increased dysfluency was associated with increased non-right-handedness, and this finding could not be explained by reference to either generalized linguistic or intellectual deficits. Results suggest individual variation in the speech motor control system in adults with Down's syndrome which may be associated with anomalous cerebral dominance.

Serving profoundly mentally retarded persons: staff attitudes and job satisfaction.

Direct-care and professional staff members who served profoundly and multiply disabled persons in 13 small community settings or in a large specialty hospital generally expressed positive attitudes regarding their jobs and resident care. Further, staff members who worked with the most disabled residents did not differ from employees serving profoundly but relatively less impaired persons. Hospital direct-care staff, however, seemed to endorse more "normalized" interpersonal relationships with residents, even though the hospital might be considered a "more restrictive" setting. It therefore appears that normalization of the physical and interpersonal environments may be somewhat independent in facilities serving profoundly disabled persons.

Structure of the Minnesota Developmental Programming System Behavioral Scales, Alternate Form C.

The Minnesota Developmental Programming System Behavioral Scales, Alternate Form C, designed to assess adaptive behavior of profoundly developmentally disabled individuals, was evaluated using data from 3,487 individuals. Relative difficulty within each of four 20-item subscales (Gross Motor, Eating, Environmental Integration, and Language/Communication) deviated slightly from the original instrument description. Factor analyses with orthogonal rotation revealed six factors with high loadings on, respectively: (a) difficult items from all subscales, (b) items from both Gross Motor and Eating subscales, (c) items from both Environmental Integration and Language/Communication subscales, and (d) items within each individual subscale except Language/Communication. Oblique rotation suggested two factors for each subscale, one loading on easier items and one loading on more difficult items. Factor patterns after oblique rotation were similar for four age groups ranging from young children (less than 5 years) to adults (over 30 years). Factor analyses of items within each subscale showed predominance of a single factor and no strong evidence of subscale multidimensionality. These results, in large part, confirmed the original Form C description.

Premature regression of adults with Down syndrome.

Adaptive skills of 2,144 individuals with Down syndrome were compared to a similar group of 4,172 developmentally disabled people without Down syndrome. Activities of daily living and cognitive skills were examined across etiology, age group, and level of mental retardation. For individuals with Down syndrome at all levels of retardation, adaptive competence declined with increasing age to a greater extent than for retarded control subjects. Clear age-related deficits associated with Down syndrome were observed only in people older than 50 years of age. Findings support previous evidence of an increased risk for the clinical signs of Alzheimer's disease among people with Down syndrome; however, signs of dementia appeared later in life than would be predicted from available neuropathological data.

Changes in explicit memory associated with early dementia in adults with Down's syndrome.

BACKGROUND: A modified version of the Selective Reminding Test (SRT) (Buschke 1973) was used to examine the changes in memory that occur with early-stage dementia of the Alzheimer's type (DAT) in adults with intellectual disability (ID) and Down's syndrome (DS), and to compare these changes to those occurring with 'normal' ageing. METHOD: Hierarchical linear modelling analyses showed steep declines in the performance of participants who had met the criteria for the onset of DAT. Non-demented participants also showed declines in performance which were related to their age. However, the absolute magnitude of these declines was consistent with a 'normal' ageing pattern and not with undetected dementia. RESULTS: In analysing the specific memory components that are compromised, the present authors found that participants with early-stage DAT showed severely diminished long-term storage and retrieval processing abilities compared to their non-demented peers. Notably, these declines preceded other symptoms of dementia, in most cases by more than a full year and sometimes by as much as 3 years. CONCLUSIONS: Thus, the present results clearly confirm that memory processes are affected during early dementia in adults with DS, and that the SRT has promise as a clinical tool.

Ageing in higher functioning adults with Down's syndrome: an interim report in a longitudinal study.

Mildly and moderately mentally retarded adults, who live in the community, were examined for global changes in mental status and specific changes in auditory and visual memory over a period of 3-5 years. Twenty-eight subjects with Down's syndrome (DS) between the ages of 27 and 55 years were compared to 18 subjects without DS who were of similar IQ and age. The evaluation of mental status consisted of testing orientation of person, place and time, object naming, visuomotor coordination, and concentration. Auditory memory was tested with an adapted version of the Buschke Memory test. Visual memory testing consisted of matching shapes which were presented simultaneously and after delays of 0, 5 and 10s on a computer-controlled screen. No changes were found in test scores between an initial testing and follow-up testing up to 5 years later, indicating that ageing processes were not having a major impact in the cognitive functioning of these subjects. Furthermore, there was no indication of any generalized decline in performance suggestive of early symptoms of dementia among the older subjects with DS.

Sequence of cognitive decline in dementia in adults with Down's syndrome.

Adults with Down's syndrome (DS) are known to be at risk of dementia of the Alzheimer type (DAT), but because of their lifelong intellectual deficits, it is difficult to determine the earliest signs and characteristics of age-associated decline and dementia. In a longitudinal study in which all participants were healthy at the time of their entry into the study, the present authors compared the amount of decline on the subtests of the WISC-R to determine the sequence of cognitive decline associated with varying stages of dementia. Twenty-two individuals with varying degrees of cognitive decline were compared to 44 adults with DS who have remained healthy. All participants functioned in the mild or moderate range of intellectual disability at initial testing. On each subtest of the WISC-R, the amount of change experienced by the healthy participants over the study period was compared to the amount of change found for each of the groups with decline. Out of the individuals who showed declines, 10 adults with DS were classified as having 'questionable' decline based on the presence of memory impairment, and five and seven adults with DS were classified as in the 'early stage' and 'middle stage' of DAT, respectively, based on the presence of memory impairment, score on the Dementia Scale for Down Syndrome and a physician's diagnosis. It was found that participants who were identified as 'questionable', in addition to the memory loss that determined their classification, also showed significant declines on the Block Design and Coding subtests. The five adults in the early stage of dementia showed declines on these subtests, and in addition, on the Object Assembly, Picture Completion, Arithmetic and Comprehension subtests. The seven adults in the middle stage of dementia showed declines on these subtests, plus declines on Information, Vocabulary and Digit Span subtests. The Picture Arrangement and Similarities subtests were not useful in distinguishing between the groups because of baseline floor effects for a substantial proportion of participants. The present longitudinal study showed a sequence of cognitive decline associated with DAT, beginning with a possible 'pre-clinical' stage, and progressing through the early and middle stages. This approach begins to define the sequence of declining cognitive capacities that contributes to the observed functional deterioration caused by Alzheimer's disease and that is likely to reflect the involvement of cortical areas as the disease progresses.

Factors related to adaptive behavior changes among profoundly mentally retarded, physically disabled persons.

Changes in adaptive competence over a 1-year period of profoundly mentally retarded, physically disabled persons living in a moderately sized residential facility or in small community programs were examined. No evidence was found to indicate that habilitative growth was greater for residents in the small community programs. Indeed, residents of the moderately sized facility showed evidence of skill acquisition whereas community residents declined slightly in adaptive skill. Within community programs, presence of a relevant goal was positively related to change in independent living skills, and clients with musculoskeletal impairments tended to regress in motor and eating skills. These data suggest that client characteristics and habilitative program content are significant predictors of client growth, and size of the residence is probably not as important for delivery of effective services.

Normal ageing in adults with Down's syndrome: a longitudinal study.

The ubiquitous presence of the neuropathology of Alzheimer disease (AD) in individuals with Down's syndrome (DS) over 40 years of age suggests that this group of people will exhibit a high prevalence of dementia of the Alzheimer type (DAT) as they age. The present study indicates that there is a clear discrepancy between the presumed presence of AD neuropathology and the clinical expression of DAT among older people with DS. In the first 6 years of a longitudinal study, the present authors compared 91 adults (31-63 years of age) with DS and mild or moderate mental retardation to 64 adults (31-76 years of age) with other forms of mental retardation (MR) on yearly measures of mental status, short- and long-term memory, speeded psychomotor function, and visuospatial organization. The results indicated that, over repeated testing on the verbal long-term memory test, younger participants with DS showed small increases in their scores, while older participants with DS showed very slight decreases. Overall performance scores on this test and a speeded psychomotor task were poorer for both diagnostic groups in individuals aged 50 years and older. The magnitude and type of these selective changes in performance were consistent with performance profiles observed in older healthy adults without mental retardation on tests measuring similar cognitive functions. Only four out of the 91 people with DS in the present sample showed changes in functioning that have led to a diagnosis of possible DAT, and in these individuals, alternative causes of performance declines were concurrently present (e.g. thyroid dysfunction). These findings indicate that some age-associated changes in functioning are related to "normal' but probably precocious ageing among adults with DS. Furthermore, these findings suggest that adults with DS and mild or moderate mental retardation may be at lower risk for dementia during their fourth and fifth decades of life than previous studies have suggested.

Localization of a human gene homologous to the PrP gene on the p arm of chromosome 20 and detection of PrP-related antigens in normal human brain.

Infectious fractions prepared from scrapie-infected hamster brains contain a protein, PrP 27-30, which shares antigenic determinants with polypeptides found in similarly prepared fractions from patients with Creutzfeldt-Jakob disease. cDNA sequences encoding the hamster PrP 27-30 identified homologous sequences in the human genome as well as in normal human brain mRNA preparations. Antibodies raised against the mouse PrP's identified antigenically related peptides in both normal hamster and human brain as well as in scrapie-infected hamster brain and CJD-affected human brain. By using in situ hybridization we localized the homologous human genomic sequences on the short arm of chromosome 20. Our results indicate that the reportedly unique proteins detected in human CJD preparations derive from normal human gene products.