American Journal of Medical Genetics Part AVolume 125A, Issue 3 p. 315-317 Research Letter Mitotic index in down's syndrome with and without dementia Edmund C. Jenkins, Corresponding Author Edmund C. Jenkins ecjenkins@erols.com Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkInstitute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314-6639.Search for more papers by this authorLingling Ye, Lingling Ye Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorShuyun Li, Shuyun Li Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorWarren B. Zigman, Warren B. Zigman Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorNicole Schupf, Nicole Schupf Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorEugene A. Sersen, Eugene A. Sersen Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorNan Zhong, Nan Zhong Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorCharles M. Miezejeski, Charles M. Miezejeski Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorSusan Sklower Brooks, Susan Sklower Brooks Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorWayne P. Silverman, Wayne P. Silverman Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this author Edmund C. Jenkins, Corresponding Author Edmund C. Jenkins ecjenkins@erols.com Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkInstitute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314-6639.Search for more papers by this authorLingling Ye, Lingling Ye Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorShuyun Li, Shuyun Li Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorWarren B. Zigman, Warren B. Zigman Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorNicole Schupf, Nicole Schupf Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorEugene A. Sersen, Eugene A. Sersen Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorNan Zhong, Nan Zhong Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorCharles M. Miezejeski, Charles M. Miezejeski Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorSusan Sklower Brooks, Susan Sklower Brooks Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this authorWayne P. Silverman, Wayne P. Silverman Institute for Basic Research in Developmental Disabilities, Staten Island, New YorkSearch for more papers by this author First published: 30 July 2003 https://doi.org/10.1002/ajmg.a.20453Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume125A, Issue315 March 2004Pages 315-317 RelatedInformation

Tau-like protein levels from 40 Down syndrome (DS) persons (31–70 years old), 40 non-DS age-matched normal controls, 18 non-DS mentally retarded (MR) persons (26–91 years old), 25 probable Alzheimer disease (AD) patients (55–99 years old) and 24 non-demented elderly controls (54–79 years old) were measured using a sandwich enzyme linked immunosorbent assay. The levels were detected in 22 of 40 DS persons and were significantly higher in DS than any other group (P<0.0001). There was no relationship between tau-like protein levels and age, gender or apolipoprotein E phenotypes in any of the five groups.

Amyloid β protein 1–40 (Aβ40) and Aβ42 levels were quantitated in plasma from 43 persons with Down syndrome (DS; 26–68 years of age), 43 age-matched normal controls, and 19 non-DS mentally retarded (MR) persons (26–91 years of age) by using a sandwich enzyme linked immunosorbent assay. Aβ40 levels were higher in DS and MR than controls, but were similar between DS and MR groups. Aβ42 levels were higher in DS than controls or MR persons. The ratios of Aβ42/Aβ40 were higher in DS than controls or MR persons. The findings are consistent with those seen in DS brains.

Brainstem auditory evoked response latencies were studied in 75 males (13 with fragile X syndrome, 18 with mental retardation due to other causes, and 44 with no disability). Latency values were obtained for each ear for the positive deflections of waves I (P1), III (P3), and V (P5). Some individuals with mental retardation required sedation. Contrary to previous report, latencies obtained for individuals with fragile X did not differ from those obtained for persons without mental retardation. Persons receiving sedation, whether or not their retardation was due to fragile X, had longer latencies for wave P5 than persons who did not receive sedation. This effect of sedation may also explain the previously reported increased latencies for persons with fragile X. Am. J. Med. Genet. 74:167–171, 1997. © 1997 Wiley-Liss, Inc.

A quantitative technique involving serial sectioning and semiautomatic morphometric analysis was used to assess the severity of the reduction in size of the major brain structures in cerebral hemispheres of children congenitally infected with HIV-1. Cerebral hemispheres from 12 children (18–48 months of age) who died of AIDS were sectioned into 5-mm-thick serial slabs and photographed. The cross-sectional areas of grossly recognizable brain structures were digitized, and the volumes were calculated according to Cavalieri’s principle. The results were compared with those of an identically processed group of control brains from non-AIDS children. Analysis of the brain weight showed that there was a significant reduction in supratentorial and infratentorial weight in the AIDS group. The results of the morphometric study revealed that the loss in brain mass was associated with a statistically significant reduction in the total volume of both hemispheres, the entire cortex, white matter, and basal ganglia. Detailed analysis of individual brain structures also showed a significant reduction in volume of all cortical regions and most of the subcortical gray matter (e.g., caudate nucleus, putamen, globus pallidus, claustrum, and thalamus). It appears that in the microencephaly observed as a frequent sequel in pediatric AIDS, the loss of brain tissue is global and includes an almost proportional loss of cortex, subcortical gray matter and white matter.

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.

Apolipoprotein E4 (apoE4) allele is strongly associated with late-onset Alzheimer's disease (AD). ApoE has been suggested to enhance the fibril formation of amyloid beta-protein. We examined the relationship of apoE phenotype to the cerebrospinal fluid (CSF) concentrations of apoE, beta-amyloid precursor protein (beta APP) and soluble amyloid beta-protein (sA beta) of 72 patients with probable AD and 72 non-demented, age-matched controls. Controls with the apoE4 allele had less CSF sA beta, on average, than controls without the apoE4 allele. No such effect was seen in AD patients. A positive correlation between CSF apoE and sA beta concentrations was found in controls and in late-onset AD patients. Individuals with apoE4 and low CSF sA beta concentrations may be susceptible to AD.

Brainstem auditory evoked response latencies were studied in 80 males (13 with Down syndrome, 23 with developmental disability due to other causes, and 44 with no disability). Latencies for waves P3 and P5 were shorter for the Down syndrome than for the other groups, though at P5, as compared to latencies for the nondisabled group, the difference was not significant. The pattern of left versus right ear responses in the Down syndrome group differed from those of the other groups. This finding was related to research noting decreased lateralization of and decreased ability at receptive and expressive language among people with Down syndrome. Some individuals required sedation. A lateralized effect of sedation was noted.

IgG subclasses were measured in sera from 33 persons with Down syndrome (DS) (mean age 55 +/- 7 years) and 33 age- and sex-matched control individuals using a mouse monoclonal antibody based sandwich enzyme linked immunosorbent assay. Significantly higher levels of IgG1 and IgG3 and lower levels of IgG2 and IgG4 subclasses were found in the DS group compared to the control individuals. The higher levels of IgG1 and IgG3 subclasses found in DS persons were consistent with those seen in patients with autoimmune diseases and chronic viral infections; the lower levels of IgG2 and IgG4 subclasses were consistent with those seen in patients with recurrent infections. Our findings are similar to those reported in children with DS. We speculate that the subclass levels may have little or no relationship to the development of brain lesions typical of Alzheimer disease in older persons with DS. There were no significant differences between the levels of IgG subclasses of persons with DS showing signs of dementia of the Alzheimer type compared to those without such manifestations.

Journal Article Brainstem auditory evoked responses in males with fragile X syndrome: Laterality and sedation effects Get access C.M. Miezejeski, C.M. Miezejeski N.Y.S. Institute for Basic Research in Developmental Disabilities, and North Shore University Hospital, Cornell University Medical College Search for other works by this author on: Oxford Academic PubMed Google Scholar G. Heaney, G. Heaney N.Y.S. Institute for Basic Research in Developmental Disabilities, and North Shore University Hospital, Cornell University Medical College Search for other works by this author on: Oxford Academic PubMed Google Scholar E.A. Sersen, E.A. Sersen N.Y.S. Institute for Basic Research in Developmental Disabilities, and North Shore University Hospital, Cornell University Medical College Search for other works by this author on: Oxford Academic PubMed Google Scholar M.S. Krawczun, M.S. Krawczun N.Y.S. Institute for Basic Research in Developmental Disabilities, and North Shore University Hospital, Cornell University Medical College Search for other works by this author on: Oxford Academic PubMed Google Scholar E.C. Jenkins, E.C. Jenkins N.Y.S. Institute for Basic Research in Developmental Disabilities, and North Shore University Hospital, Cornell University Medical College Search for other works by this author on: Oxford Academic PubMed Google Scholar W.T. Brown W.T. Brown N.Y.S. Institute for Basic Research in Developmental Disabilities, and North Shore University Hospital, Cornell University Medical College Search for other works by this author on: Oxford Academic PubMed Google Scholar Archives of Clinical Neuropsychology, Volume 7, Issue 4, 1992, Pages 349–350, https://doi.org/10.1093/arclin/7.4.349a Published: 01 July 1992

We measured beta 2-microglobulin (beta 2-M), soluble interleukin-2 receptor (sIL-2R), and soluble CD8 (sCD8) antigen levels in paired cerebrospinal fluid (CSF) and sera from patients with subacute sclerosing panencephalitis (SSPE), multiple sclerosis (MS), and other neurological diseases (OND) using enzyme-linked immunosorbent assay. beta 2-M was significantly increased in CSF of the SSPE group compared to the MS or the OND group. Similarly, beta 2-M in the MS versus OND group was significantly increased in CSF. Although serum levels of beta 2-M were similar in the three groups, the CSF/serum ratios were higher in SSPE versus the MS group and in the MS versus the OND group. Levels of sIL-2R and sCD8 were higher in SSPE CSF than OND CSF; however, there were no differences between levels in SSPE and MS CSF. The levels of sIL-2R were increased in SSPE sera compared to those of MS or the OND group, whereas levels of sCD8 in serum from the three groups were similar. The findings of increased CSF/serum ratio of beta 2-M and higher levels of serum sIL-2R and CSF sCD8 in SSPE patients are consistent with those seen in patients with acute and chronic viral infections. When the levels between the initial and follow-up CSF and serum samples from SSPE patients were compared, the data showed that CSF levels of sCD8 elevated during periods of clinical worsening and decreased during clinical improvement. In contrast, serum beta 2-M decreased during periods of worsening and increased during improvement. The measurement of serum beta 2-M and CSF sCD8 may be useful in SSPE patients as markers to monitor disease activity.

We have evaluated 62 fragile X syndrome [fra(X)] individuals (55 males and 7 females) with different degrees of developmental disabilities that were clinically non-progressive and non-focal in character. The mean age for the 55 males was 23.1 years +/- 14.3 SD with a range of 2-70: for the 7 females, the mean age was 15.7 years +/- 3.5 SD with a range of 10-20 years. Mental retardation (MR) was found in 53 males (8/53 [15.1%] mild, 26/53 [49.1%] moderate, 14/53 [26.4%] severe, and 5/53 [9.4%] profound). Learning disabilities were found in 2/55 (3.6%) of males. One of the 7 females had mild and one had moderate MR: the other 5 were learning disabled. Autistic stigmata were present in 10/62 (16%) of the patients. Only 14/62 (23%) had a history of seizures, all of which were controlled with anticonvulsants. In 36/62 cases, an electroencephalogram (EEG) was performed. We compared these data with that of others. Brain stem auditory evoked response (BAER) was performed in 12 cases. Abnormalities were found in only 5/12. Neuroimaging and computerized cranial transaxial tomography (CT scan) were performed on 21/62 (34%) of the patients. Only 8 of these 21 (38%) studies were abnormal. One patient died; neuropathological studies showed mild brain atrophy, with light microscopic and ultrastructural abnormalities. Rapid Golgi dendritic spine patterns showed that the proximal apical segments were abnormally developed. Very thin, long tortuous spines with prominent terminal heads and irregular dilatations were present. Marked reductions in the length of the synapses, as determined on EPTA-postfixed tissue where noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Brainstem auditory-evoked responses (BAER) were obtained from 46 control, 16 Down's syndrome, and 48 autistic male subjects. Six Down's syndrome and 37 autistic subjects were tested with sedation. Sedated and unsedated Down's syndrome subjects displayed shorter absolute and interpeak latencies for early components of the BAER whereas the sedated autistic group showed longer latencies for the middle and late components. The prolongation of latencies in the sedated autistic group was unrelated to age or intellectual level. Although individuals requiring sedation may have a higher probability of neurological impairment, an effect of sedation on the BAER cannot be ruled out.

Numerous intraneuronal neurofibrillary tangles and senile (neuritic) plaques are the two characteristic lesions in Alzheimer disease (AD) and adult Down syndrome (DS). Evidence indicates that microtubule assembly is impaired in AD. We studied spindle microtubule repolymerization rates in EBV-transformed lymphoblasts from AD, DS, and control individuals after colcemid exposure. The distinctive arrangement of microtubules in spindle and its size make this structure an obvious choice for study. Recovery trends in the three patient groups differed significantly; in particular, the controls showed an earlier appearance of intact spindle microtubules than AD. Other researchers found similar results using AD fibroblasts. The results from the DS cells were inconsistent and difficult to interpret. It is unclear how the AD microtubules differ from controls, or whether a relationship exists between the altered microtubule repolymerization kinetics observed in this study and the presence of neurofibrillary tangles in AD patients. A difference in repolymerization rates can be the basis for a diagnostic test for AD if it can be verified.

We have found similarities of skull shape, brain growth and brain maturation in 17 DS and 10 non-DS (control) fetuses, ages 15-22 weeks of gestational age (Group A), and differences in 101 DS and 80 non-DS cases, from birth to 60 months (Group B). Postnatally, the gross neuropathological differences between DS and control brains are more distinct after 3-5 months of age. The anterior posterior diameter fronto-occipital length of the brain hemispheres is shortened and that is secondary to reduction of frontal lobe growth. Also flattening of occipital poles, narrowing of the superior temporal gyruses and generalized retardation of brain growth were common findings. Standard morphometric methods indicate changes from birth [Wisniewski et al. 1984, 1986, 1990]. The cerebral cortex of the DS cases had a 20-50% reduction of neurons since birth, mainly in the granular layers [Wisniewski et al. 1984, 1986, 1990]. Changes in brain weight with age were greater in the non-DS than in the DS cases, and greater in males than in females. CHD and GI malformations were associated with less brain weight in both DS and non-DS cases. We suggest that the prenatal retardation of neurogenesis begins after 22 weeks' gestational age. The postnatal retardation of brain growth is secondary to pre- and postnatal abnormalities in synaptogenesis.