MRI volumes of the hippocampus and amygdala in adults with Down's syndrome with and without dementia

OBJECTIVE: This study sought to determine whether volumes of the hippocampus and amygdala are disproportionately smaller in subjects with Down's syndrome than in normal comparison subjects and whether volume reduction is greater in Down's syndrome subjects with dementia. METHOD: The subjects were 25 adults with Down's syndrome (eight with dementia) and 25 cognitively normal adults who were individually matched on age, sex, and race. Magnetic resonance imaging measures included volumes of the hippocampus, amygdala, and total brain. Nineteen of the Down's syndrome subjects had follow-up scans (interscan interval = 9-41 months). RESULTS: Nondemented Down's syndrome subjects had significantly smaller volumes of the hippocampus, but not the amygdala, than their comparison subjects, even when total brain volume was controlled for. Volumes of both the hippocampus and the amygdala were smaller in the demented Down's syndrome subjects than in their comparison subjects, even when total brain volume was controlled for. Age was not correlated with volume of the hippocampus or amygdala among the nondemented Down's syndrome subjects and the comparison subjects; age was correlated with volume of the amygdala, but not the hippocampus, among the Down's syndrome subjects with dementia. Changes in volume over time were not statistically significant for either the demented or the nondemented subjects. CONCLUSIONS: Hippocampal volume, while disproportionately small for brain size in individuals with Down's syndrome, remains fairly constant through the fifth decade of life in those without dementia. All subjects over age 50 who had Down's syndrome demonstrated volume reduction in the hippocampus as well as clinical signs of dementia. Dementia was also associated with volume reductions in the amygdala that exceeded reductions in total brain volume.     

Pattern-reversal visual evoked potentials in Down's syndrome

We examined pattern-reversal visual evoked potentials (PRVEPs) in 36 adult patients with Down's syndrome, and analyzed the effects of the opthalmological abnormalities on results of PRVEPs. The P100 latency was significantly delayed in 24 eyes of 16 patients. The P100 latency was significantly longer and its amplitude was significantly smaller (P < 0.001) in Down's syndrome patients than in age-matched normal controls. In 9 patients without any ophthalmological abnormalities, P100 latency showed no significant difference from that in normal controls, but three of them showed a significant delay of P100. Their P100 amplitudes were significantly smaller than those in normal controls. Therefore, we considered that the ophthalmological abnormalities are one of the main factors causing PRVEPs abnormalities in Down's syndrome patients, but some unknown factors should be also responsible.     

Assessment of counseling practices at the birth of a child with Down's syndrome.

An attempt was made to analyze 414 parents' perceptions of their experiences at the birth of their child with Down's syndrome. The interpretation of the results and the parents' comments suggest that the counseling of parents with a newborn Down's syndrome child demands tact, truthfulness, and empathetic guidance. The parents should be informed of the child's condition in a kind and sensitive manner as soon as the diagnosis of Down's syndrome has been made. Appropriate terminology should be employed, and both parents should be present when the physician tells them of their misfortune. Unconditional recommendations of institutionalization of the child with Down's syndrome should be practices of the past. The professionals' thoughtful considerations and mature counsel should assist constructively in shaping the child's future.     

Aortic regurgitation and mitral valve prolapse with Down's syndrome: a case-control study

ABSTRACT. This case-control study was designed to determine whether aortic regurgitation (AR) and mitral valve prolapse (MVP) are specifically associated with Down's syndrome, or occur in a comparably retarded population without Down's syndrome. The 92 control subjects resided at the same institution as the 131 cases, and had mental retardation attributable to low birth weight or perinatal asphyxia. Mean (±SD) ages of the cases and the control group were 41 × 11 years compared with 40 × 13 years, respectively. The relative risk of AR among the cases (those with Down's syndrome) was 2.9 (95% confidence interval, 0.65–13.2; P=0.16) and that of MVP was 3.5 (95% confidence interval, 1.2–10.2; P =0.02). The results showed that these two valvular abnormalities are specifically associated with Down's syndrome in adults.     

Eating behavior,prenatal and postnatal growth in Angelman syndrome

The objectives of the present study were to investigate eating behavior and growth parameters in Angelman syndrome. We included 39 patients with Angelman syndrome. Twelve cases had a larger Class I deletion, eighteen had a smaller Class II deletion, whereas paternal uniparental disomy (pUPD) or a verified UBE3A mutation were present in five and four cases, respectively. Eating behavior was assessed by a questionnaire. Anthropometric measures were obtained from medical records and compared to Danish reference data. Children with pUPD had significantly larger birth weight and birth length than children carrying a deletion or a UBE3A mutation. We found no difference in birth weight or length in children with Class I or Class II deletions. When maternal birth weight and/or birth weight of siblings were taken into consideration, children with Class I deletion had a lower weight at birth than expected, and the weight continued to be reduced during the investigated initial five years of life. In contrast, children with pUPD showed hyperphagic behavior and their weight increased significantly after the age of two years. Accordingly, their body mass index was significantly increased as compared to children with a deletion. At birth, one child showed microcephaly. At five years of age, microcephaly was observed in half of the deletion cases, but in none of the cases with a UBE3A mutation or pUPD. The apparently normal cranial growth in the UBE3A and pUPD patients should however be regarded as the result of a generally increased growth. Eating behavior, pre- and postnatal growth in children with Angelman syndrome depends on genotype.     

Small cerebral hemispheres in adults with Down's syndrome: contributions of developmental arrest and lesions of Alzheimer's disease

Morphometric analysis was used to measure cross-sectional areas of cerebral structures in middle-aged patients with Down's syndrome (N = 5) for comparison with data obtained from individuals with senile dementia of the Alzheimer type (N = 16) and neuropathologically normal controls (N = 14). Down's syndrome was distinguished from Alzheimer's disease by the 19% lower mean brain weight which was associated with more pronounced reductions in the areas of both cortex and white matter. However, the differences were most striking in the anterior frontal and anterior temporal regions where the effects of arrested neurodevelopment are grossly evident. In addition, in Down's syndrome the amygdala was significantly smaller than in Alzheimer's disease. In both Down's syndrome and Alzheimer's disease, shrinkage of the cortical ribbon was associated with abundant neuritic plaques and neurofibrillary tangles, while white matter atrophy was associated with histopathological evidence of axonal degeneration. These findings suggest that in Down's syndrome the reduction in volume in the posterior portion of the cerebrum relative to controls is largely due to acquired lesions of Alzheimer's disease, whereas anteriorly and within certain subcortical nuclei, the effects of both Alzheimer's disease and arrested neurodevelopment are manifested. Moreover, the finding of white matter lesions in Down's syndrome corroborates the notion that white matter degeneration is a fundamental component of the Alzheimer's disease process.     

Intelligence levels of Down's syndrome children.

Intelligence levels of a sample of 180 Down's syndrome children were reported, and the results indicated that their abilities are not as limited as previously thought. The introduction of special developmental programs from birth onwards appears to have promoted an increase in intellectual development. Lack of extended educational opportunity may account for the apparent decrease in intellectual function in Down's syndrome adolescents. It is suggested that school placement be based on demonstrated present ability rather than assumed long-term potential inferred from autosomal and physical characteristics.     

Hormonal and biochemical disturbances in Down's syndrome

ABSTRACT. Clinical and laboratory endocrine variables in 29 adult institutionalized patients with Down's syndrome were compared with those of matched controls consisting of other mentally retarded patients from the same institution. Of the clinical variables, testes volume and body height were significantly lower in patients with Down's syndrome than in control patients. The thyroid function tests documented a higher average TSH level in Down's syndrome than in other mentally retarded patients. However, there was no clear-cut correlation between TSH and thyroid hormone levels. The data indicate that there is a tendency towards primary thyroid dysfunction in Down's syndrome. In addition, there is some evidence indicating a relative failure of TSH secretion. In male patients, estradiol was elevated compared to controls. FSH and LH also seemed slightly higher in the study group, but the differences only reached statistical significance when patients on chronic medication were omitted. Prolactin was significantly greater in the Down's syndrome patients than in the controls, both over the entire sample and in the subgroup of men with Down's syndrome, with P -values of around 0.001. The elevation of prolactin was not due to medication and did not correlate to thyroid function or difficulties during blood sampling. In females, the difference was not statistically significant. Laboratory tests that may be associated with endocrine disease or might indicate disease which could influence the endocrine status, were also included in this study. Compared with the controls, ESR, creatinine and uric acid levels were higher in Down's syndrome patients, while albumin was lower, all with P-values lower than 0.001. Vitamin B₁₂ was moderately lower in Down's syndrome patients than in controls (P<0.05).     

Parent's perception of social and sexual functions in adolescents with Down's syndrome

ABSTRACT. The authors investigated parental perceptions of social interactions, interest in the opposite sex, sexual functions and issues concerning sex education in young persons with Down's syndrome. The evaluation of the data revealed that more than half of the study population showed interest in the opposite sex and are attending social gatherings. Many of the youngsters had expressed a desire to get married, however, only a few had an interest in sexual relationships. Masturbation was observed in 40% of the young men and in 22% of the young women. About half of the parents feel that their children should be sterilized or should have other forms of birth control if they would be able to reproduce. Only a limited number of adolescents had sex education. More parents who have girls with Down's syndrome than those who have boys are worried that their child may be taken advantage of sexually.     

Cerebral metabolic pattern in young adult Down's syndrome subjects: altered intercorrelations between regional rates of glucose utilization

ABSTRACT. Correlations between regional cerebral metabolic rates for glucose determined by pisitron emission tomography with [¹⁸F]-2-fluoro-2-deoxy-D-glucose, have heen used to indicate functional associations between pairs of brain regions. This method was applied to data from 14 healthy adult subjects with trisomy 21 Down's syndrome tape < 34 years) and from 24 age-matched healthy controls. Correlations were obtained between ratios of regional-to-global resting glucose utilization. In comparison to age-matched controls, the Down's svndrome group had many smaller correlations for region-pairs wilhin and between the frontal and parietal lubes, some correlations were large and negative in the Down's syndrome group, but large and positive in the controls. One region so affected was the inferior frontal gyrus thai includes Broca's area. This result is consistent with ihe relatively greater language impairment in Down's syndrome subjects. The thalamus also had smaller correlations with temporal and occipital regions in the Down's syndrome group compared: to controls. These results suggest that Down's syndrome is accompanied by a functional disruption of neural circuits associated with directed attention.     

Neuroanatomy of Down's syndrome: a high-resolution MRI study

OBJECTIVE: Down's syndrome, the most common genetic cause of mental retardation, results in characteristic physical and neuropsychological findings, including mental retardation and deficits in language and memory. This study was undertaken to confirm previously reported abnormalities of regional brain volumes in Down's syndrome by using high-resolution magnetic resonance imaging (MRI), determine whether these volumetric abnormalities are present from childhood, and consider the relationship between neuroanatomic abnormalities and the cognitive profile of Down's syndrome. METHOD: Sixteen children and young adults with Down's syndrome (age range=5-23 years) were matched for age and gender with 15 normal comparison subjects. High-resolution MRI scans were quantitatively analyzed for measures of overall and regional brain volumes and by tissue composition. RESULTS: Consistent with prior imaging studies, subjects with Down's syndrome had smaller overall brain volumes, with disproportionately smaller cerebellar volumes and relatively larger subcortical gray matter volumes. Also noted was relative preservation of parietal lobe gray and temporal lobe white matter in subjects with Down's syndrome versus comparison subjects. No abnormalities in pattern of brain asymmetry were noted in Down's syndrome subjects. CONCLUSIONS: The results largely confirm findings of previous studies with respect to overall patterns of brain volumes in Down's syndrome and also provide new evidence for abnormal volumes of specific regional tissue components. The presence of these abnormalities from an early age suggests that fetal or early postnatal developmental differences may underlie the observed pattern of neuroanatomic abnormalities and contribute to the specific cognitive and developmental deficits seen in individuals with Down's syndrome.     

High brain myo-inositol levels in the predementia phase of Alzheimer's disease in adults with Down's syndrome: a 1H MRS study

OBJECTIVE: An extra portion of chromosome 21 in Down's syndrome leads to a dementia in later life that is phenotypically similar to Alzheimer's disease. Down's syndrome therefore represents a model for studying preclinical stages of Alzheimer's disease. Markers that have been investigated in symptomatic Alzheimer's disease are myoinositol and N-acetyl-aspartate. The authors investigated whether abnormal brain levels of myo-inositol and other metabolites occur in the preclinical stages of Alzheimer's disease associated with Down's syndrome. METHOD: The authors used 1H magnetic resonance spectroscopy (MRS) with external standards to measure absolute brain metabolite concentrations in 19 nondemented adults with Down's syndrome and 17 age- and sex-matched healthy comparison subjects. RESULTS: Concentrations of myoinositol and choline-containing compounds were significantly higher in the occipital and parietal regions of the adults with Down's syndrome than in the comparison subjects. Within the Down's syndrome group, older subjects (42-62 years, N = 11) had higher myo-inositol levels than younger subjects (28-39 years, N = 8). Older subjects in both groups had lower N-acetylaspartate levels than the respective younger subjects, although this old-young difference was not greater in the Down's syndrome group. CONCLUSIONS: The approximately 50% higher level of myo-inositol in Down's syndrome suggests a gene dose effect of the extra chromosome 21, where the human osmoregulatory sodium/myo-inositol cotransporter gene is located. The even higher myoinositol level in older adults with Down's syndrome extends to the predementia phase earlier findings of high myoinositol levels in symptomatic Alzheimer's disease.     

Vitamin A gastrointestinal absorption in persons with Down's syndrome

ABSTRACT. The total daily vitamin A intake, physical signs associated with vitamin A deficiency, and the response to a vitamin A challenge were studied in 33 patients with Down's syndrome and in 14 intellectually normal persons (comparison group). The evaluation of detailed dietary histories revealed that the study subjects' mean daily vitamin A intake was similar to the recommended daily allowance for adults and that there was no significant difference of the mean daily vitamin A intake between study and comparison groups (5029 IU and 5706 IU, respectively). Subjects with Down's syndrome had more symptoms usually seen in patients with hypovitaminosis A than the persons in the comparison group. The baseline serum vitamin A levels in the Down's syndrome and comparison groups were within the normal range (106.0 μg/dl and 136.5 μg/dl, respectively). The vitamin A absorption curve of persons with Down's syndrome paralleled that of normal individuals and no significant difference of vitamin A levels between study and comparison groups was observed except for the 6-h values. Also, the absorption differential (     -0-h value) did not show a significant difference between the two groups. Thus, these investigations do not support previous reports of significantly decreased vitamin A absorption in individuals with Down's syndrome.     

Decline in cerebral glucose utilisation and cognitive function with aging in Down''s syndrome.

The cerebral metabolic rate for glucose (CMRglc) was measured with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose in 14 healthy subjects with Down's syndrome, 19 to 33 years old, and in six healthy Down's syndrome subjects over 35 years, two of whom were demented. Dementia was diagnosed from a history of mental deterioration, disorientation and hallucinations. All Down's syndrome subjects were trisomy 21 karyotype. CMRglc also was examined in 15 healthy men aged 20-35 years and in 20 healthy men aged 45-64 years. All subjects were at rest with eyes covered and ears plugged. Mean hemispheric CMRglc in the older Down's syndrome subjects was significantly less, by 23%, than in the young Down's syndrome group; statistically significant decreases in regional metabolism (rCMRglc) also were present in all lobar regions. Comparison of the younger control group with the older control group showed no difference in CMRglc or any rCMRglc (p greater than 0.05). Assessment of language, visuospatial ability, attention and memory showed significant reductions in test scores of the old as compared with the young Down's syndrome subjects. These results show that significant age differences in CMRglc and rCMRglc occur in Down's syndrome but not in healthy controls, and that, although only some older Down's syndrome subjects are demented, significant age reductions in neuropsychologic variables occur in all of them.     

Middle-latency somatosensory evoked potentials following median and posterior tibial nerve stimulation in Down's syndrome.

Middle-latency somatosensory evoked potentials (SEPs) following median and posterior tibial nerve stimulation were studied in 40 patients with Down's syndrome and in age- and gender-matched healthy controls as well as in middle-aged and aged healthy subjects. In median nerve SEPs, latencies of the initial cortical potentials, N18 and P18, showed no significant difference, but the following potentials N22, P25, N32, P41 and P46 were relatively or significantly shorter in latency in Down's patients than in the controls. Amplitudes of all components in Down's patients were significantly larger than those of age- and gender-matched controls as well as of those of middle-aged healthy subjects, but there was only a small difference in their amplitudes from aged healthy subjects. Results of posterior tibial nerve SEPs were generally consistent with those of median nerve SEPs. Therefore, 'short latency with large amplitude' is the main characteristic of middle-latency SEPs in Down's syndrome, possibly related to accelerated physiological aging of the central nervous system.     

Verbal and nonverbal interaction of mothers with their down's syndrome and nonretarded infants.

While it appears probable that parental expectancies due to early knowledge of the condition of Down's syndrome in infants affects parent-child interactions, little data are available showing how interactions are affected. In an observational, laboratory-based study, we compared verbal and nonverbal interactions between 10 mothers and their Down's syndrome infants and 10 mothers and their nonretarded infants. Although there was no difference between the groups in mothers' language complexity, mothers of Down's syndrome children spoke at a significantly faster rate. Observational measures of infants showed that Down's syndrome babies smiled and vocalized less, but mothers in the two groups failed to differ significantly on the nonverbal interactional behavior observed. The results were discussed in relation to the conclusions of other investigators who have speculated that language delays in Down's syndrome children may be due in part to differences in the environment provided by caregivers.     

Studies of antithyroid antibodies in Down's syndrome.

The presence of antithyroid antibodies (antithyroglobulin and antimicrosomal) in serum of patients with Down's syndrome and their respective mothers were studied based on data from the literature, showing a possible correlation between the presence of these antibodies in the serum of mothers and the birth of mongoloid children. Antithyroid antibodies were studied in 40 patients with Down's syndrome, with ages ranging from 5 months to 21 years old, 24 males and 16 females and in the respective mothers whose ages varied from 22 to 66 years. In none of the analyzed sera of the mongoloids as well of their mothers, the authors were able to detect the antithyroid antibodies studied.     

Relation of medial temporal lobe volumes to age and memory function in nondemented adults with Down's syndrome: implications for the prodromal phase of Alzheimer's disease.

OBJECTIVE: In Down's syndrome (trisomy 21), a dementia syndrome occurs that is phenotypically similar to Alzheimer's disease; the initial phase is characterized by memory loss. The authors used an in vivo structural technique in the predementia stage of Alzheimer's disease in adults with Down's syndrome to investigate whether atrophy of medial temporal lobe structures occurs in these subjects and whether volumes of these structures correlate specifically with performance on memory tests. METHOD: The subjects were 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women and 17 men) and 33 healthy comparison subjects (mean age=41.3, 15 women and 18 men). By using T(1)-weighted magnetic resonance imaging slices taken perpendicular to the Sylvian fissure, volumes of the hippocampus, amygdala, anterior and posterior parahippocampal gyrus, and temporal pole CSF were measured in both hemispheres. These data were normalized to the total intracranial volume. RESULTS: For Down's syndrome, smaller volumes of the right and left amygdala, hippocampus, and posterior parahippocampal gyrus were significantly associated with greater age; this association was not seen in the anterior parahippocampal gyrus. The amygdala and hippocampus volumes were positively correlated with memory measures. For the comparison group, there was no relationship between volume and age in any region. CONCLUSIONS: In the predementia phase of Down's syndrome, significant volume changes in medial temporal lobe structures occur with age and are related to memory. These structures are affected early in Alzheimer's disease in Down's syndrome, and their evaluation may help identify people in the preclinical stages of Alzheimer's disease.     

Comparative coherence studies in healthy volunteers and Down's syndrome patients from childhood to adult age.

Within the scope of the Munich Pediatric Longitudinal Study, EEG coherence was studied in 212 Down's syndrome patients and 342 healthy controls aged from 6 months up to 30 years. The digitalized EEG records were subjected to spectral analysis. Frequency band-related coherences were calculated to reveal age-specific differences in the functional relationship between two brain areas in Down's syndrome patients and controls. The results show that in the "eyes-open" state the intra-hemispheric coherence in the alpha band was significantly lower (P less than 0.05) in the Down's syndrome patients than in the controls whereas that in the delta bands it was generally higher. The intra-hemispheric coherence in the "eyes-closed" state was generally higher in the Down's syndrome groups than in the controls; however, significant differences could be detected only in some age groups. The age-specific development of coherence in the inter-hemispheric parieto-occipital region was almost identical in Down's syndrome children as in controls, both with open and closed eyes. The most distinct differences were found in the fronto-central inter-hemispheric coherence (P less than 0.01), while the coherence deficiencies in the Down's syndrome group became more prominent with increasing age from school age onwards. These electrophysiological results are compared with the results of neuropathological and neurophysiological studies of other authors. It can be suggested that there are correlations with a significantly small number of dendritic spines in Down's syndrome patients, which was determined in neuropathological examinations. A neuronal model of interpretation is presented which explains the increasing developmental deficit with age in Down's syndrome children.