We have detected consistently shorter telomeres associated with MCI in older adults with DS using 8 methods/measurements: (1) chromosome 1 telomere light intensity alone; (2) chromosome 21 telomere light intensity alone; (3) chromosome 1 telomere: cen 2 light intensity ratio; (4) chromosome 21 telomere: cen 2 light intensity ratio; (5) total telomere light intensities measured in interphase; (6) numbers of chromosome arms with no detectable signal; (7) actual physical lengths of chromosome 1 telomeres; and (8) ratios of chromosome 1 telomere length to the remainder of chromosome 1. As expected based on previously reported preliminary results [Jenkins et al, 2010
], all measures included in the present study indicated that MCI was associated with telomere shortening. However, there were important differences among these methods with respect to the differentiation between individuals with and without MCIDS, suggesting that some specific measures have greater promise than others as biomarkers of clinical status.
For all “simple” measures of light intensity (1, 2, 5, and 6, above), some minimal overlap in measurements was observed between groups, indicating that any specific measurement value chosen as a classification criterion would have excellent but imperfect specificity or sensitivity. The use of the cen 2 probe as a standard eliminated these overlaps and represented a step in the right direction, but the separation between groups of approximately 1 S.D. still suggests that a best case criterion, while having excellent validity, would again be unlikely to have perfect sensitivity and specificity.
Our findings for “direct” linear measurements in microns were more promising. Just over 2S.D.s separated the longest chr 1 telomere length from a case with MCIDS (3.1 microns) from the shortest non-demented case (3.9 microns), and this separation increased to over 4S.D.s when the remainder of chr 1 was used as a standard (MCIDS = 0.14 and Non-demented = 0.20, S.D. = 0.012; see ). This large degree of separation between distributions for affected and unaffected individuals suggests that a classification criterion of 0.17 for this ratio measure is very likely to have near perfect sensitivity and specificity throughout the population of older adults with DS. Of course, that value will need to be confirmed in a validation study, but even should adjustment be needed, it seems clear that this method of measurement will provide an informative biomarker of clinical status for this high-risk and diagnostically challenging population. This would be especially important for differential diagnosis in situations where a treatable condition presents clinically as a pseudo-dementia, but even in true cases of Alzheimer’s disease, the objective confirmation of status would allow more effective planning for support needs.
In addition, our experience indicates that the physical measurement of chromosome length also had a relatively fast turnaround time, with data acquisition completed in approximately 6 hours for an individual case. Only light intensity telomere analysis of interphase preparations required less time, but these preparations had reduced sensitivity (). It is possible (future studies are needed to validate this opinion) that only short-arm linear measurements could be used (for chromosome 2, for example, already identified with the cen 2 probe) and thus significantly reduce turnaround times. Physically measuring the telomere length in microns should also be feasible without the expensive software required to quantify light intensity. Most simply, the magnified images of chromosomes could be printed and telomere lengths could be measured with a precision caliper. Alternatively, the PNA telomere probe might be labeled with horse radish peroxidase, visualized using bright field microscopy, and measurements could be made from either black and white images on prints or directly, with the use of a stage and ocular micrometer.
These findings provide compelling evidence that shorter telomere length in short-term T lymphocyte cultures from people with DS can serve as a biomarker for the presence of MCI as well as dementia [Jenkins et al, 2006
]. While the empirical association between telomere length and clinical status is clearly evident within the older populations of adults with DS (Jenkins et al., 2008
, present study), the biological mechanism(s) responsible for this association remain unknown. In fact, we do not yet know if shorter telomeres represent a risk factor, with individuals having shorter telomeres more likely to develop dementia, or a biomarker, with telomere length decreasing as the underlying Alzheimer’s disease progresses. Additional longitudinal assessments of telomere length are needed to distinguish between these two possibilities.
The association between telomere length and clinical status does not appear to be unique to DS.Panossian et al. (2003)
first described a comparable relationship for the general population. Subsequent studies confirmed these findings with respect to dementia although results focusing on MCI have been mixed (Hochstrasser et al., 2012
; Movérare-Skrtic et al., 2012
). Our study has been limited to people with DS and may not be generalizable to other populations, but we believe it adds to the evidence indicating that measures of telomere length in T cells can be an informative part of diagnostic evaluations in all cases of suspected AD.