One hundred brains of patients with Down's syndrome (DS) who died in institutions for chronic care were examined for clinicopathological correlation of Alzheimer's disease. Fifty-one were below and 49 were above age 30 years at death. Tissues from the right, prefrontal, and hippocampal cortices were processed for microscopy using H&E and Bodian-periodic acid-Schiff impregnation. Morphometric evaluations of plaques and tangles were carried out. Plaques or plaques and tangles were found in the brains of 56 patients with DS, 7 below age 30 and 49 above that age. A history of dementia was evident in the medical records of 15 of these patients; of these only 2 were below the age of 30. The brains of the patients with DS who also had clinical dementia had more than twenty plaques or plaques and tangles per 1.5 X 10(6) micron 2 of cortex. The numbers of plaques and tangles found in the brains of the patients with DS above the age of 30 greatly increased with age but varied from brain to brain. These observations suggest a correlation among dementia, the density of plaques and tangles, and age. All 100 brains studied showed early arrest of brain growth and brain atrophy, a condition that may have been due to prenatal arrest of neurogenesis mainly in the granular cell layers, prenatal and postnatal arrest of synaptogenesis, and early aging. Plaques and tangles developed twenty to thirty years earlier and dementia was clinically detected at least three times more frequently (20 to 30%) in DS than it is known to occur in the non-DS population.

Fragile X [fraX] syndrome is a common hereditary disorder associated with a fragile site marker at Xq27.3 which clinically presents as a form of mental retardation (MR). Postmortem investigation of 3 fraX positive males with mild to moderate MR did not document any gross neuropathological changes. Golgi analysis of neocortical dendritic spine morphology extended our previous observations of immature, long, tortuous spines in one adult case of fraX (Rudelli, et al., Acta Neuropathologica 67:289-295, 1985) to 2 new cases. Evidence for similar dendritic spine abnormalities was found, although Golgi analysis was less than optimal because of incomplete dendritic stain impregnation. Neocortical intra-layer cell density was also investigated in all 3 cases. Cresyl violet stained neurons were counted in 10 randomly selected fields in neocortical layers II-VI of cingulate and temporal association areas (Brodmann's areas 23 and 38). Neuron counts in fraX and control neocortex showed no significant differences. Thus, abnormal dendritic spine morphology with preservation of neuronal density appears to characterize the neocortex in individuals with this common form of mental retardation.

All Down syndrome (DS) children have different degrees of developmental disabilities, developmental delay, and developmental brain abnormalities associated with CNS maturation delay and cortical dysgenesis. We have examined 780 occipitofrontal circumferences (OFC), mean and r SD, of DS children from birth to age 5 years. Also, gross and microscopic neuropathological studies in the same age group were performed, with special attention to brain weight (BW), shape, myelin formation, cortical organization of 101 DS and 80 non-DS individuals; ultrastructural studies were also performed on selective cases (five DS and five non-DS). The OFC was plotted on Nellhause curves and showed microcranium after mid-infancy in most cases. Twenty percent of DS children had an OFC in the lower normal range. The brain shape in DS newborn infants was the same as in non-DS infants, but after 3-5 months of age in DS infants the antero-posterior diameter was found to be shorter than in non-DS infants. Narrowness of the superior temporal gyrus was noted in 34 of 101 (33%) of DS brains. Microscopic examination showed myelination delay in 22.5% DS and only in 6.8% non-DS children. Morphometric studies in DS cases from birth showed fewer neurons (20-50% less), lower neuronal densities, and neuronal distribution, especially of cortical layers I1 and IV. Ultrastructurally in DS, the synaptic density, synaptic length, and contact zones were found to be abnormal. The retardation of brain growth, maturation delay, and cortical dysgenesis present in DS children most likely are regulated by the extra chromo-

Article abstract-Clinical and neuropathologic evidence points to the development of Alzheimer's disease (AD) in seven Down's syndrome patients above age 40. Dementia was observed in these patients over periods of 2.5 to 9.2 years. The first clinical sign of AD, visual memory loss, was succeeded by impaired learning capacity and decreased occupational and social functioning, and culminated in seizures and urinary incontinence. The morphometric observations of the brains of these seven patients with AD showed that the numbers of plaques and tangles exceeded 20 per 1.5 X 10" pm2 area, in both the prefrontal and hippocampal cortices. Plaques and tangles were also evident in the basal ganglia, thalamus, hypothalamus, and midbrain. In addition, we found that four of the seven brains showed small strokes, and five of the seven amyloid angiopathy. This study also indicates that by longitudinal neuropsychological evaluations and lab tests, which exclude other causes of dementia, the diagnosis of AD can be made even in severely and profoundly retarded patients. NEUROLOGY 1985;35:957-961 Alzheimer's disease in Down's syndrome:Clinicopathologic studies Clinical documentation of AD in DS patients has been made largely by retrospective studies. Moreover, the patients studied who were often institutionalized with profound mental retardation, provided conflicting information in that estimates of AD changes varied from 15%H to 27%" "'to 100%." In a prospective study'j covering 10 years, clinical evidence of AD was seen in 12 of 49 DS patients above age 40 years (24%).We now provide a clinicopathologic description of seven patients with DS with documented clinical manifestations of Alzheimer's dementia extending from 2.5 to 9.2 years before death. Materials and methods. Clinical methods. Cognitivefunctions, defined as learning capacities and memory functions, were assessed quantitatively on a repeated, follow-up basis for five of the seven patients, using methods developed previously.' I I h To minimize the effects of environmental (test) conditions, each patient was examined with the same test materials under conditions as nearly identical as possible in a specially equipped mobile laboratory. T o rule out causes of memory and learning incapacities unrelated to Alzheimer's disease, control studies were performed with different patients and examiners.'4,'A Neurologic examination for focal and frontal release signs were conducted by D.R. Crapper McLachlan. Other clinical data used to estimate "overall regression" were obtained from personal reports by staff and from medical records. Neurologic examinations were conducted on an irregular basis two or three times before death. Cognitive assessments were conducted between two and six times, a t approximately lllr-year intervals.Criteria for inclusion in the study (excluding patient 5) were normal birth record, no prior recorded history of seizures, no gross sensory or motor impairment, and no evidence of focal neurologic signs.Gross and microscopic neuropathologic methods. Each br...

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.