COVER FIGURE The cover image, by Edmund C. Jenkins et al., is based on the Research Article Longitudinal telomere shortening and early Alzheimer's disease progression in adults with down syndrome, DOI: 10.1002/ajmg.b.32575.

Abstract 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.

Telomere shortening was shown to parallel Alzheimer's disease (AD) associated dementia. By using a dual PNA Probe system we have developed a practical method for comparing telomere length in T-lymphocyte interphases from individuals with Down syndrome (DS) with and without "mild cognitive impairment" (MCI-DS) and demonstrated that telomere length can serve as a valid biomarker for the onset of MCI-DS in this high-risk population. To verify progressive cognitive decline we have now examined sequential changes in telomere length in 10 adults with DS (N = 4 Female, N = 6 Male) developing MCI-DS. Cases were selected blind to telomere length from a sample of adults with DS previously enrolled in a prospective longitudinal study at 18-month intervals with clinical and telomere assessments: (1) MCI-DS group data were collected approximately three years prior to development of MCI-DS; (2) 18 months later; (3) when MCI-DS was first observed. These telomere measures were compared to those from another 10 adults with DS matched by sex and approximate age but without indications of MCI-DS (Controls). PNA (peptide nucleic acid) probes for telomeres together with a chromosome two centromere probe were used. Findings indicated telomere shortening over time for both Cases and Controls. Group differences emerged by 18-months prior to recognition of MCI-DS onset and completely non-overlapping distributions of telomere measures were observed by the time of MCI-DS onset. This study adds to accumulating evidence of the value of telomere length, as an early biomarker of AD progression in adults with Down syndrome.

Previous studies have suggested that Alzheimer's disease (AD) causes an accelerated shortening of telomeres, the ends of chromosomes consisting of highly conserved TTAGGG repeats that, because of unidirectional 5′–3′ DNA synthesis, lose end point material with each cell division. Our own previous work suggested that telomere length of T‐lymphocytes might be a remarkably accurate biomarker for “mild cognitive impairment” in adults with Down syndrome (MCI‐DS), a population at dramatically high risk for AD. To verify that the progression of cognitive and functional losses due to AD produced this observed telomere shortening, we have now examined sequential changes in telomere length in five individuals with Down syndrome (3F, 2M) as they transitioned from preclinical AD to MCI‐DS (N = 4) or dementia (N = 1). As in our previous studies, we used PNA (peptide nucleic acid) probes for telomeres and the chromosome 2 centromere (as an “internal standard” expected to be unaffected by aging or dementia status), with samples from the same individuals now collected prior to and following development of MCI‐DS or dementia. Consistent shortening of telomere length was observed over time. Further comparisons with our previous cross‐sectional findings indicated that telomere lengths prior to clinical decline were similar to those of other adults with Down syndrome (DS) who have not experienced clinical decline while telomere lengths following transition to MCI‐DS or dementia in the current study were comparable to those of other adults with DS who have developed MCI‐DS or dementia. Taken together, findings indicate that telomere length has significant promise as a biomarker of clinical progression of AD for adults with DS, and further longitudinal studies of a larger sample of individuals with DS are clearly warranted to validate these findings and determine if and how factors affecting AD risk also influence these measures of telomere length. © 2015 Wiley Periodicals, Inc.

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.

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.

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.

American Journal of Medical Genetics Part AVolume 158A, Issue 5 p. fm i-fm v Table of ContentsFree Access Table of Contents, Volume 158A, Number 5, May 2012 First published: 19 April 2012 https://doi.org/10.1002/ajmg.a.35452AboutPDF 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 Volume158A, Issue5May 2012Pages fm i-fm v RelatedInformation

Pent-4-en-1-amines are reactive to fluoroalkyl iodides with respect to sodium dithionite initiated free radical addition reactions. We report here the development of a novel and efficient synthesis of 2-fluoroalkyl pyrrolidine derivatives by sodium dithionite initiated one-pot reaction of pent-4-en-1-amines bearing various protecting groups with fluoroalkyl iodides. Among which, the N-benzyl-pent-4-en-1-amine exhibited the best tolerance toward the reaction condition in the present study, affording the desired adducts 3 in moderate to good yields of 65–85%.

4-Fluoroalkyl-2-acylamino-4-butyrolactones were afforded in moderate yields by the sodium dithionite initiated one-pot addition-lactonization reaction of polyfluoroalkyl iodides with 2-acylamino-4-pentenoic acids.

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.

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.

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.

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. © 2008 Wiley‐Liss, Inc.

We have previously reported that cultured T-lymphocytes from women with Down syndrome (DS) and Alzheimer's Disease (AD)/dementia have shorter telomeres, chromosome ends consisting of highly conserved TTAGGG repeats, than their peers without AD/dementia (Neurobiol Aging 2006;27:942). To extend our previous findings and to determine if any measures of telomere length could provide diagnostically useful information regarding AD status. Adults with Down syndrome were classified with respect to dementia status based upon recommended criteria (Amer J Ment Retard 2004;109:111). Cases were age- and sex-matched such that one individual within each pair had either AD/dementia or a status comparable (in many respects) to mild cognitive impairment (MCI) in the general population, abbreviated here as MCI-DS, and the other did not. Forty T-lymphocyte metaphases (20) and interphases (20) per individual were analyzed to detect shorter or absent telomeres as indicated by fluorescent light intensity differences after FISH with a peptide nucleic acid (PNA) probe. All chromosomes, as well as some single chromosomes, were examined. Significantly shorter telomeres were found in a total of 15 people (our original sample plus six new cases) with AD/dementia and were also observed in four females with MCI-DS. Interestingly, we have also found that a simple count of the total number of signals from all telomeres is reduced in people with AD/Dementia. Finally, we found that single chromosomes, especially chromosome 21, have shorter telomeres in people with DS/AD/Dementia and MCI-DS and, most importantly, there was no overlap in some measures between people with DS/AD/Dementia or MCI-DS versus peers classified as “not demented.” Findings that telomere length can distinguish among groups with and without dementia/MCI-DS suggest that we may have found a biomarker for AD. However, we need to confirm and extend these results before making firm conclusions. Should replication be successful, it could provide a basis for development of a diagnostic procedure with both high sensitivity and specificity, permitting future treatments to be targeted most effectively. Supported by Alzh. Assoc. grants IIRG-99–1598, IIRG-96–077, NIH grants R01-AG014763, P01-HD35897, R01-HD37425, R01-AG07232, and by NYS OMRDD.

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

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.