In order to treat individuals with Down syndrome (DS) better and more efficiently and to gain more insights on its relation to Alzheimer's disease (AD), a comprehensive understanding is needed for its progression in the early or preclinical phase using various biomarkers. DS is a significant risk factor for the early development of AD, with plaques and tangles typically developing by age 35. A better understanding is needed of early markers of the disease in DS patients. Additionally the DS population represents a unique group - due to this elevated risk for AD - to examine biomarkers that may translate in general outside of the DS population to individuals at risk for developing late onset AD. In this proposal, the researchers will assess the longitudinal changes of various biomarkers in a cohort of individuals similar in design to the cross-sectional sectional study in the preliminary data.
This study will recruit from three experimental groups: (1)The DS (adult) group will consist of 15 DS subjects aged 21 and older who do not qualify for the diagnosis of dementia at the beginning of the study. (2)The DS/AD group will consist of 15 DS subjects aged 40 and older who do qualify for the diagnosis of dementia by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Diagnoses will be by standard consensus review of all cases. (3)Normal control (NC) adult will consist of 10 cognitively normal, non-DS individuals, age-matched to the DS group. Blood will be collected to assess apolipoprotein E (ApoE) genotype. Participation in the dried blood spot collection (DBSC) will be an optional sub-study. Only participants and/or their caregivers/legally authorized representatives indicating they wish to have DBSC performed on the consent will provide specimens.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
DIAGNOSTIC
Masking
NONE
Enrollment
19
Blood: ApoE genotyping, comprehensive metabolic panel, RNA sequencing. Urine: beta-hCG (human corionic gonadotropin) testing.
Dementia Questionnaire for People with Learning Disabilities; Mini-Mental State Examination; Severe Impairment Battery; Vineland Adaptive Behavior Scale; Arizona Memory Assessment for Intellectual Disability; Kaufman Brief Intelligence Test; Nepsy Mazes; and, Timed Up and Go.
Used in small doses to image brain amyloid-beta deposits in human beings. Radioactivity necessary to create the positron emission tomography (PET) images. Radiation exposure is slightly more than a person would receive from a routine clinical head computed tomography scan.
Magnetic resonance imaging of the head and brain.
Injected intravenously during a PET scan and is a marker for the tissue uptake of glucose; a radiopharmaceutical compound.
Administered during a PET, in small amounts, necessary to create the scan images. Radioactive. The total amount of radiation is about the same that a patient receives from a routine abdominal/pelvis computerized tomography.
A non-invasive method of monitoring human rest and activity cycles. A small actigraph unit is worn to measure gross motor activity. The unit is usually worn on the wrist.
St. Joseph's Hospital and Medical Center
Phoenix, Arizona, United States
Florbetapir PET - change between timeframes
The researchers will use multi-modal partial least squares (MMPLS) to integrate the volumetric MRI, tau PET, FDG PET and florbetapir PET data and investigate the potential for increased sensitivity to examine the longitudinal changes related to both brain structure and fibrillar amyloid depositions. The MMPLS based subject scores, which is free from multiple comparisons, will be the primary measure integrating information from imaging modalities. The combined primary measures will be used each to compute the number of DS or DS/AD patients in the treatment and in the placebo arms needed for a 60 month clinical trial with 80% power, two-tailed p=0.05 and assumed treatment effects of 25%. These estimated samples are indicative of each biomarker for their sensitivity.
Time frame: Year 1, Year 2-3
tau PET - change between timeframes
The researchers will use multi-modal partial least squares (MMPLS) to integrate the volumetric MRI, tau PET, FDG PET and florbetapir PET data and investigate the potential for increased sensitivity to examine the longitudinal changes related to both brain structure and fibrillar amyloid depositions. The MMPLS based subject scores, which is free from multiple comparisons, will be the primary measure integrating information from imaging modalities. The combined primary measures will be used each to compute the number of DS or DS/AD patients in the treatment and in the placebo arms needed for a 60 month clinical trial with 80% power, two-tailed p=0.05 and assumed treatment effects of 25%. These estimated samples are indicative of each biomarker for their sensitivity.
Time frame: Year 1, Year 2-3
FDG PET - change between timeframes
The researchers will use multi-modal partial least squares (MMPLS) to integrate the volumetric MRI, tau PET, FDG PET and florbetapir PET data and investigate the potential for increased sensitivity to examine the longitudinal changes related to both brain structure and fibrillar amyloid depositions. The MMPLS based subject scores, which is free from multiple comparisons, will be the primary measure integrating information from imaging modalities. The combined primary measures will be used each to compute the number of DS or DS/AD patients in the treatment and in the placebo arms needed for a 60 month clinical trial with 80% power, two-tailed p=0.05 and assumed treatment effects of 25%. These estimated samples are indicative of each biomarker for their sensitivity.
Time frame: Year 1, Year 2-3
MRI - change between timeframes
The researchers will use multi-modal partial least squares (MMPLS) to integrate the volumetric MRI, tau PET, FDG PET and florbetapir PET data and investigate the potential for increased sensitivity to examine the longitudinal changes related to both brain structure and fibrillar amyloid depositions. The MMPLS based subject scores, which is free from multiple comparisons, will be the primary measure integrating information from imaging modalities. The combined primary measures will be used each to compute the number of DS or DS/AD patients in the treatment and in the placebo arms needed for a 60 month clinical trial with 80% power, two-tailed p=0.05 and assumed treatment effects of 25%. These estimated samples are indicative of each biomarker for their sensitivity.
Time frame: Year 1, Year 2-3
dried blood spot collection (DBSC) analysis - change between timeframes
(a) Detect and track RNA biomarkers longitudinally from a single dried blood spot (DBS) using next generation RNA sequencing (RNA-Seq) in prospectively assessed DS, DS/AD and NC, (b) Study and identify biomarkers with the greatest rate of change in DS patients who are at differential risk levels for the development of AD dementia, and (c) Correlate the RNA biomarkers with imaging (FDG-PET, FBP (Florbetapir F18)-PET, MRI, tau PET) that are concurrently being gathered in the proposed study populations.
Time frame: Year 1, Year 2-3
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