Lingling Ye

New York State Institute for Basic Research in Developmental Disabilities, New York City, NY, United States

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Publications (19)34.23 Total impact

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    ABSTRACT: Previously, we established that short-term T lymphocyte cultures from people with Down syndrome (DS) and dementia (Alzheimer's disease) had shorter telomeres than did those from age- and sex-matched people with DS only, quantified as significantly reduced numbers of signals of peptide nucleic acid (PNA) telomere probes in whole metaphases [Jenkins et al. (2008); Neurosci Lett 440:340-343] as well as reduced telomere probe light intensity values in interphases [Jenkins et al. (2010); Neurobiol Aging 31:765-771]. We now describe shorter telomere length in adults with DS and mild cognitive impairment (MCI) compared to age- and sex-matched individuals with DS without MCI. Telomere length is quantified by reduced telomere signal numbers and shorter chromosome 1 telomeres measured in micrometers (microns). These findings were in agreement with quantitative light intensity measurements of chromosome 1 and chromosome 21 PNA telomere probes with and without the use of a "normalizing ratio" involving the fluorescence exhibited by a PNA probe for centromere 2, and with the use of light intensity measurements of interphase preparations. Most importantly, the distributions of chromosome 1 telomere lengths (in microns) were completely non-overlapping for adults with and without MCI, indicating that this measure has great promise as a biomarker for MCI as well as dementia in this population.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 05/2012; 159B(5):598-604. · 3.23 Impact Factor
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    ABSTRACT: We reported previously that 10 older men (66.4 ± 4.6 years) with premutation alleles (55-200 CGG repeats) of the FMR1 gene, with or without FXTAS, had decreased telomere length when compared to sex- and age-matched controls. Extending our use of light intensity measurements from a telomere probe hybridized to interphase preparations, we have now found shortened telomeres in 9 younger male premutation carriers (31.7 ± 17.6 years). We have also shown decreased telomere length in T lymphocytes from 6 male individuals (12.0 ± 1.8 years) with full mutation FMR1 alleles (>200 CGG repeats). These findings support our hypothesis that reduced telomere length is a component of the sub-cellular pathology of FMR1-associated disorders. The experimental approach involved pair-wise comparisons of light intensity values of 20 cells from an individual with either premutation or full mutation CGG-repeat expansions relative to an equivalent number of cells from a sex- and age-matched control. In addition, we demonstrated reduced telomere size in T-lymphocyte cultures from eight individuals with the FMR1 premutation using six different measures. Four relied on detection of light intensity differences, and two involved measuring the whole chromosome, including the telomere, in microns. This new approach confirmed our findings with light intensity measurements and demonstrated the feasibility of direct linear measurements for detecting reductions in telomere size. We have thus confirmed our hypothesis that reduced telomere length is associated with both premutation and full mutation-FMR1 alleles and have demonstrated that direct measurements of telomere length can reliably detect such reductions.
    American Journal of Medical Genetics Part A 04/2012; 158A(5):1060-5. · 2.30 Impact Factor
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    ABSTRACT: We have observed evidence of increased telomere shortening in short-term T-lymphocyte cultures following freezing and thawing of the original inoculum obtained by ficoll-paque gradient centrifugation, compared to T-lymphocytes that were cultured immediately without freezing and thawing from the same blood sample from 3 female and 3 male adults. Because freezing may have similar effects on other cell types, and because telomere shortening may only manifest its effects after many years or decades, we suggest there is a pressing need for evaluation of the effects of freezing on any cells envisioned for clinical applications, including embryo implantation.
    Cryobiology 03/2012; 65(1):72-3. · 2.14 Impact Factor
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    ABSTRACT: We have recently reported reduced telomere length in T lymphocytes of individuals with Down syndrome (DS) and dementia due to Alzheimer's disease (AD). We have now replicated and extended that study by finding that people with DS and mild cognitive impairment (MCI-DS) also have shorter telomeres than people with DS without MCI-DS. Additional new findings demonstrated that light intensity measurements from chromosome 21 alone, or in concert with chromosomes 1, 2, and 16, exhibited shorter telomeres in adults with DS and with either dementia or MCI-DS compared to aging per se. Chromosome 21 measurements appeared to be especially promising for use as a biomarker because there was no overlap in the distribution of light intensity measurement scores between demented or MCI-DS and non-demented participants. Given that early clinical symptoms of AD can be very difficult to recognize in this population of adults due to their pre-existing cognitive impairments, a valid biomarker would be of great value. Early detection is especially important because it would allow treatments to begin before significant damage to the central nervous system has occurred. Our findings suggest that it may be feasible to use telomere shortening as a biomarker for accurately inferring dementia status.
    Neurobiology of aging 05/2010; 31(5):765-71. · 5.94 Impact Factor
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    ABSTRACT: We have reported previously that telomeres (ends of chromosomes consisting of highly conserved TTAGGG repeats) were shorter in metaphase and interphase preparations in T lymphocytes from short-term whole blood cultures of women with Down syndrome (DS) and dementia compared to age-matched women with DS but without dementia [E.C. Jenkins, M.T. Velinov, L. Ye, H. Gu, S. Li, E.C. Jenkins Jr., S.S. Brooks, D. Pang, D.A. Devenny, W.B. Zigman, N. Schupf, W.P. Silverman, Telomere shortening in T lymphocytes of older individuals with Down syndrome and dementia, Neurobiol. Aging 27 (2006) 41-45]. Our previous study was carried out by measuring changes in fluorescence intensity [using an FITC-labeled peptide nucleic acid (PNA) probe (Applied Biosystems; DAKO) and Applied Imaging software], and we now report on a substantially simpler metric, counts of signals at the ends of chromosomes. Nine adults with DS and dementia plus four who are exhibiting declines in cognition analogous to mild cognitive impairment in the general population (MCI-DS) were compared to their pair-matched peers with DS but without dementia or MCI-DS. Results indicated that the number of chromosome ends that failed to exhibit fluorescent signal from the PNA telomere probe was higher for people with dementia or mild cognitive impairment (MCI-DS). Thus, a simple count of chromosome ends for the "presence/absence" of fluorescence may provide a valid biomarker of dementia status. If this is the case, then after additional research for validation to assure high specificity and sensitivity, the test may be used to identify and ultimately guide treatment for people at increased risk for developing mild cognitive impairment and/or dementia.
    Neuroscience Letters 09/2008; 440(3):340-3. · 2.03 Impact Factor
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    ABSTRACT: The authors present a case study of a 70-year-old man with Down syndrome ("Mr. C.") who they followed for 16 years and who does not exhibit declines in cognitive or functional capacities indicative of dementia, despite having well-documented, complete trisomy 21. The authors describe the age-associated changes that occurred over 16 years as well as provide detailed information regarding Mr. C.'s health and genetic status. To further emphasize Mr. C.'s successful aging, the authors compared his longitudinal performance profile with that of 2 peers of comparable level of intellectual functioning: 1 similar-aged man with clinical Alzheimer's disease and a younger man who was healthy. The authors present potential explanations for the phenotypic variability observed in individuals with Down syndrome.
    Intellectual and developmental disabilities 07/2008; 46(3):215-28. · 1.44 Impact Factor
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    ABSTRACT: Reduced telomere length has recently been reported in T lymphocytes of individuals with trisomy 21 Down syndrome (DS) and dementia. Shorter telomeres also have been documented in dyskeratosis congenita, cell senescence, Alzheimer disease, and neoplastic transformation. These observations suggest that similar shortening may occur in people with fragile X-associated tremor/ataxia syndrome (FXTAS), which frequently is accompanied by dementia. To test this hypothesis, telomere length has been quantified in T lymphocytes from older male carriers of premutation FMR1 alleles, with or without FXTAS, and FXTAS with dementia. Shorter telomeres (relative to age-matched controls) were observed in 5/5 individuals with FXTAS and dementia, in 2/2 individuals with FXTAS without dementia, and in 3/3 individuals with the fragile X premutation only (P values ranged from <0.001 to <0.05; Student's t-test), indicating that telomere shortening is associated with the premutation expansion of the FMR1 gene. The current study design allowed simultaneous comparisons among control, premutation, FXTAS, and FXTAS with dementia samples, and showed nearly equal degrees of shortening relative to controls among the three premutation sample groups. Thus, telomere shortening may serve as a biomarker for cellular dysregulation that may precede the development of the symptoms of FXTAS.
    American Journal of Medical Genetics Part A 06/2008; 146A(12):1543-6. · 2.30 Impact Factor
  • Article: P-039
    Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2007; 3(3).
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    ABSTRACT: Telomere shortening has been recently correlated with Alzheimer's disease status. Therefore, we hypothesized that a possible association might exist for adults with Down syndrome (DS). Using blind, quantitative telomere protein nucleic acid FISH analyses of metaphase and interphase preparations from 18 age-matched trisomy 21 female study participants with and without dementia, we have observed increased telomere shortening in adults with DS and dementia (p < .01). From this initial study, we conclude that telomere shortening is associated with dementia in this high-risk population and suggest that additional research may show that telomere shortening may be a biological marker of dementia status.
    Neurobiology of Aging 07/2006; 27(7):941-5. · 6.17 Impact Factor
  • American Journal of Medical Genetics Part A 04/2004; 125A(3):315-7. · 2.30 Impact Factor
  • Neurobiology of Aging - NEUROBIOL AGING. 01/2004; 25.
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    ABSTRACT: Fragile X syndrome is recognized as the most common inherited cause of mental retardation in western countries. The prevalence of the fragile X syndrome in Asian populations is uncertain. We report a multi-institutional collaborative study of molecular screening for the fragile X syndrome from 1,127 Chinese mentally retarded (MR) individuals. We found that 2.8% of the Chinese MR population screened by DNA analysis had the fragile X full mutation. Our screening indicated that the fragile X syndrome prevalence was very close to that of Caucasian subjects. In addition, we found that 62.5% of fragile X chromosomes had a single haplotype for DXS548-FRAXAC1 (21-18 repeats) which was present in only 9.7% of controls. This unique distribution of microsatellite markers flanking the FMR1 CGG repeats suggests that the fragile X syndrome in Chinese populations, as in the Caucasian, may also be derived from founder chromosomes.
    American Journal of Medical Genetics 06/1999; 84(3):191-4.
  • American Journal of Medical Genetics 06/1999; 84(3):309-10.
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    ABSTRACT: To determine whether there is an association of polymorphic variants of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) and autistic spectrum disorders, we analyzed the 5-HTTLPR genotypes of 72 autistic subjects, 11 fragile X syndrome patients with autistic behavior, 43 normal subjects, and 49 fragile X syndrome non-autistic subjects. The distribution frequency of 5-HTTLPR long allele (L) and the short allele (S) variants showed no differences between subjects. Our findings do not support the hypothesis that polymorphic 5-HTTLPR variants are a susceptibility factor for autistic disorders.
    Neurogenetics 05/1999; 2(2):129-31. · 3.58 Impact Factor
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    ABSTRACT: Fragile X syndrome is recognized as the most common inherited cause of mental retardation in western countries. The prevalence of the fragile X syndrome in Asian populations is uncertain. We report a multi-institutional collaborative study of molecular screening for the fragile X syndrome from 1,127 Chinese mentally retarded (MR) individuals. We found that 2.8% of the Chinese MR population screened by DNA analysis had the fragile X full mutation. Our screening indicated that the fragile X syndrome prevalence was very close to that of Caucasian subjects. In addition, we found that 62.5% of fragile X chromosomes had a single haplotype for DXS548-FRAXAC1 (21-18 repeats) which was present in only 9.7% of controls. This unique distribution of microsatellite markers flanking the FMR1 CGG repeats suggests that the fragile X syndrome in Chinese populations, as in the Caucasian, may also be derived from founder chromosomes. Am. J. Med. Genet. 84:191–194, 1999. © 1999 Wiley-Liss, Inc.
    American Journal of Medical Genetics 04/1999; 84(3):191 - 194.
  • American Journal of Medical Genetics 04/1999; 84(3):309 - 310.
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    ABSTRACT: Alzheimer's disease (AD), a progressive neurodegenerative disorder, is diagnosed definitively by increased numbers of beta-amyloid plaques and neurofibrillary tangles in brain biopsy or autopsy specimens. There are no simple straightforward laboratory tests currently available for clinical diagnosis. We have found consistent reduction in mitotic index levels in skin fibroblast cultures from AD individuals compared with age- and sex-matched controls. These differences were enhanced by overnight exposure to colcemid (p = 0.04). Results suggest that mitotic index in skin fibroblasts cultures should be further investigated as a potential diagnostic indicator for AD.
    Neuroreport 01/1999; 9(17):3857-61. · 1.40 Impact Factor
  • Neuroreport 01/1998; 9(17):3857-3861. · 1.40 Impact Factor
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    ABSTRACT: Previous studies of founder chromosome effects in fragile X have been based on linkage disequilibrium with either FRAXAC1 or DXS548 alone or combined with FRAXAC2. Recently, we found no linkage disequilibrium of FMR-1 with FRAXAC2, but rather, found FRAXAC2 was complex and highly mutable. Therefore, we have now analyzed FRAXAC1 and DXS548 together for haplotypes, two markers which have not been jointly analyzed previously, to test for disequilibrium. We typed 315 fragile X (FX) chromosomes and controls, further subdivided into large controls (LC) and small controls (SC) with < or = 35 repeats and identified 26 different haplotypes. Two were more frequent and one less frequent in FX than SCs, thus confirming apparent linkage disequilibrium in fragile X. However, we noted increased FX microsatellite heterozygosity, either individually (results quite similar to previous studies) or as haplotypes. This heterozygosity covaried with FX > LC > SC, which may indicate alternative explanation exists for the apparent disequilibrium. We hypothesize that large FMR-1 CGG repeat allele genes may be associated with the generation of new microsatellite mutations. Possible mechanisms include gene conversions between CGG repeats and flanking microsatellites involving unequal double cross-overs, the expansion of small control CGGs to larger sizes associated with episodic generalized microsatellite instability or as a direct result of mutant FMR-1 gene function. We conclude that the founder effects observed with the use of these CA repeats is likely to reflect both linkage disequilibrium and increased microsatellite instability of fragile X chromosomes.
    American Journal of Medical Genetics 07/1994; 51(4):405-11.