Aging and Dementia in Adults with Down Syndrome

Principal Investigator: Wayne Silverman

This ongoing NIH supported Program Project will be renewed for another five years, and is programmatically a seamless continuation of my current Exempt protocol (#NA_00002225; "Changes in Functioning Among Mentally Retarded Adults"). The overarching objectives of this program of research will remain unchanged: (1) to study the basic biological mechanisms that underlie Alzheimer disease (AD), focusing explicitly on the adult population with Down Syndrome (DS); (2) to quantitatively document the clinical progression in this unique population; (3) to validate assessment methods and classification criteria with the potential for use in clinical service settings, and (d) to determine genetic and epigenetic factors contributing to the DS phenotype. The title of the grant has now been changed in response to a need to delete the term "mentally retarded," which is no longer consistent with current usage within the field.

The general methods also remain unchanged, although there have been minor revisions that will have no effect on risks or benefits (e.g., informant interviews have been updated but participation time is comparable; sample size has been increased (up to 800 adults); study duration has been extended to allow further longitudinal study of participants, although the frequency of assessments is the same (at 14-20 month intervals). Of course, specific aims have been updated, building upon our previous progress. Nevertheless, procedures for data collection will be in all critical respects unchanged as far as participants are concerned.

As before, the results of this research will have clear practical value for improving diagnosis of dementia in adults with DS. The methods are also designed to identify avenues that can be pursued in the rational development of strategies for treatment and prevention of AD.

With one small exception (see below), program operations will continue to be based in New York State and the broader NYC metropolitan area due to the fact that participants remained in place despite the relocation of the P.I. to KKI in 2006. Thus, this continues a large, integrated and multifaceted program of research focused on developmental aging and dementia of the Alzheimer type (DAT) within the population with Down syndrome through 2015. All assessments of human subjects conducted at institutions other than the Kennedy Krieger Institute (or any facility of Johns Hopkins University) will either be identical to or modified subtly from those employed for over a decade. (For examples of changes, different assays are planned for blood samples but the collection process will remain unchanged (routine venipuncture with volume 50 ml or less); direct cognitive assessments and staff interviews will have some additions and deletions but the general features of the procedures will remain unchanged).

Participants will now be adults with Down syndrome (total N equal to or less than 800). All (except those at KKI/Hopkins as specified below) undergo a formal evaluation, which includes: (1) clinical record reviews; (2) staff interviews regarding functional abilities and dementia symptoms; (3) cognitive assessment; (4) collection of blood samples; and (5) physical/neurological evaluation (in select cases). All these procedures will continue to be conducted by staff of the New York State Institute for Basic Research in Developmental Disabilities (IBR) through the Assessment Core described in the uploaded grant application. The IRB at IBR has served as the lead IRB for this research thus far, and approved this research study (document also uploaded).

The only involvement of participants here at KKI/Hopkins will entail the limited participation of a small subsample (N equal to or less than 40) of adults with Down syndrome between the ages of 21 and 30. These adults will be enrolled through the Down Syndrome Clinic at the Kennedy Krieger Institute. Participation for each of these adults will only involve a one-time review of clinic charts and drawing of a blood sample via routine venipuncture (approximately 20 ml but never more than 50 ml). The chart summaries and blood samples will be sent to Columbia University, New York, NY for analyses once all personal identifiers have been deleted and records/samples are given a unique participant ID number. Anonymized data and blood samples collected by colleagues in New York will also continue to be distributed to the respective Principal Investigators of the four continuing program Subprojects.

Below are brief descriptions of each component of the program project grant.

Subproject 1. “Features of Metabolic syndrome and risk for Alzheimer’s disease among adults with Down syndrome;” Warren Zigman, P.I.; New York State Institute for Basic Research in Developmental Disabilities.

This Subproject will examine the confluence of symptoms known as the metabolic syndrome within our target population to determine if specific measures are related to individual differences in risk for dementia. Peripheral insulin can cross the blood brain barrier and may contribute to increased deposition of Aβ as well as tau protein phosphorylation, both of which are key aspects of AD neuropathology. Thus, it is biologically plausible to suspect that insulin resistance and other features of the metabolic syndrome may increase risk for AD.

Subproject 2. “Validation of criteria for identifying “Mild Cognitive Impairment” in adults with Down syndrome;” Sharon Krinsky-McHale, Co-P.I.; New York State Institute for Basic Research in Developmental Disabilities, and Wayne Silverman, Co-P.I., Kennedy Krieger Institute and Johns Hopkins University School of Medicine.

Mild cognitive impairment (MCI) is defined clinically as a state of mild impairment that is: (a) intermediate between declines associated with lifespan brain aging and the deficits that occur in conjunction with dementia, and (b) does not interfere notably with activities of daily living (although functional declines may occur in instrumental activities of daily living). For individuals with DS (or ID due to any other cause), recognition of MCI can be especially difficult given the presence of lifelong cognitive impairments of varying degrees. While the notion of MCI as a transitional stage between cognitive normality and dementia is easy to grasp, no standards currently exist for operationally defining this construct in populations with substantial pre-existing cognitive impairments. We believe such methods will be of increasing importance as treatments targeting the progression of AD are developed, and therefore we propose to characterize the cognitive status associated with MCI using criteria that are conceptually similar to those adopted by for use within the general population.

Subproject 3. “Epigenetic Modifiers in Down syndrome;” Benjamin Tycko, P.I.; Columbia University Medical Center.

A striking feature of Down syndrome (DS; trisomy 21; +21) is the wide range of phenotypic severity. In most cases the genetic or epigenetic factors underlying this variation, and indeed the pathogenesis of the phenotypes themselves, remain largely unknown. Here we hypothesize that the relevant tissues in people with +21 may have accumulated altered patterns of DNA methylation on chromosome 21 and on other chromosomes, potentially affecting some or all of these phenotypes. In this highly interactive project we will carry out MSNP and Illumina Infinium assays on peripheral blood leukocyte (PBL) DNAs from people with DS spanning a wide range of ages, including a unique collection of the oldest old survivors, comparing the results with normal controls spanning the same age range. In parallel, we will carry out direct functional studies of the highest priority differentially methylated genes using cell culture and mouse models.

Subproject 4. “Genetic epidemiology of Alzheimer’s disease in Down syndrome;” Nicole Schupf and Joseph Lee, Co-P.I.s; Columbia University Medical Center.

In previous work, we made several key observations that support the hypothesis that genetic and environmental factors can contribute to age at onset and risk of AD in DS. We now propose to determine the contribution of additional genetic variants that may influence cognitive function, risk for AD, age at onset of AD, and differences in Aβ peptide levels in a large cohort of adults with DS from our current project. We will take advantage of the deep phenotyping and repeated assessments that have been accomplished since the inception of this study. Our previous work places us in a unique position to relate genetic variants to a range of AD-related phenotypes, and this will allow us to conduct an analysis of a broad panel of candidate genes for AD in adults with DS. We will fine map candidate genes using the Illumina GoldenGate custom array.

Cores 1 & 2: Administration Core and Assessment Core.

These two large Cores continue as the nucleus of our Program Project. The Cores are responsible for Program administration and management. This includes stimulation and coordination of interactions among all Program subcomponents. In addition, Program participants are characterized employing a Core assessment battery that includes reviews of medical records, interviews with knowledgeable informants, cognitive testing, and neurological evaluation (for a small group of incident dementia cases). The Assessment is also responsible for collecting blood samples. All of this work is conducted under the auspices of IBR, with the approval of that IRB, with the exception of the subsample of adults enrolled through the Down Syndrome Clinic at KKI, as mentioned above.

Core 3: Genetics Core.

This Core continues to provide investigators with cytogenetic confirmation of DS whenever these results cannot be found in medical records, and for documenting APOE genotype. In addition, the Core maintains archives of DNA and frozen cells of our participants as it establishes immortal cell lines. Together with the detailed characterization of these people provided by other Program components, these resources will be of enormous value for our current and future investigations as new biomarkers are identified as possible diagnostic indicators or risk factors. The Core also collaborates closely with the activities of Subprojects 3 and 4, providing cytogenetic characterization of both human and mouse material. All the activities of this Core are conducted at IBR with the approval of that IRB.