Relationship Between Down Syndrome (DS) and Alzheimer's Disease (AD)

NCT02759887 | Completed

• 1 other identifier: PHX-16-0028-70-03
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Down Syndrome; Alzheimer's Dementia

Outcome Measures

Primary Outcomes (4)

• 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.

  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.

  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.

  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.

  Year 1, Year 2-3

Secondary Outcomes (1)

• dried blood spot collection (DBSC) analysis - change between timeframes

  Year 1, Year 2-3

Study Arms (3)

DS adult group

OTHER

Consists of 15 DS subjects aged 21 and older who do not qualify for the diagnosis of dementia at the beginning of the study. Interventions include biospecimen collection, cognitive assessments, caregiver questionnaire, Florbetapir F18 imaging, MRI, Fludeoxyglucose F18 (FDG), Tau Pet, Actigraphy.

Procedure: biospecimen collection; Other: cognitive assessments; Other: caregiver questionnaire; Procedure: Florbetapir F18 imaging; Procedure: MRI; Procedure: Fludeoxyglucose F18 (FDG); Procedure: Tau Pet; Procedure: Actigraphy

DS/AD group

OTHER

Consists of 15 DS subjects aged 40 and older who do qualify for the diagnosis of dementia by DSM-IV criteria. Diagnoses will be by standard consensus review of all cases. Interventions include biospecimen collection, cognitive assessments, caregiver questionnaire, Florbetapir F18 imaging, MRI, Fludeoxyglucose F18 (FDG), Tau Pet, Actigraphy.

Procedure: biospecimen collection; Other: cognitive assessments; Other: caregiver questionnaire; Procedure: Florbetapir F18 imaging; Procedure: MRI; Procedure: Fludeoxyglucose F18 (FDG); Procedure: Tau Pet; Procedure: Actigraphy

NC adult

OTHER

Consists of 10 cognitively normal, non-DS individuals, age-matched to the DS adult group. Interventions include biospecimen collection, cognitive assessments, Florbetapir F18 imaging, MRI, Fludeoxyglucose F18 (FDG), Tau Pet, Actigraphy.

Procedure: biospecimen collection; Other: cognitive assessments; Procedure: Florbetapir F18 imaging; Procedure: MRI; Procedure: Fludeoxyglucose F18 (FDG); Procedure: Tau Pet; Procedure: Actigraphy

Interventions

biospecimen collection PROCEDURE

Blood: ApoE genotyping, comprehensive metabolic panel, RNA sequencing. Urine: beta-hCG (human corionic gonadotropin) testing.

DS adult group; DS/AD group; NC adult

cognitive assessments OTHER

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.

DS adult group; DS/AD group; NC adult

caregiver questionnaire OTHER

DS adult group; DS/AD group

Florbetapir F18 imaging PROCEDURE

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.

DS adult group; DS/AD group; NC adult

MRI PROCEDURE

Magnetic resonance imaging of the head and brain.

DS adult group; DS/AD group; NC adult

Fludeoxyglucose F18 (FDG) PROCEDURE

Injected intravenously during a PET scan and is a marker for the tissue uptake of glucose; a radiopharmaceutical compound.

DS adult group; DS/AD group; NC adult

Tau Pet PROCEDURE

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.

Also known as: F-AV-1451

DS adult group; DS/AD group; NC adult

Actigraphy PROCEDURE

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.

Also known as: actimetry

DS adult group; DS/AD group; NC adult

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects with free Trisomy 21.
• Male or female subjects who are 21 years of age or older.
• Subjects who are not diagnosed with possible or probable AD or dementia after evaluation NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer's Disease and Related Disorders Association) criteria.
• Subjects who live with or have regular visits from a responsible caregiver willing to provide information about the subject's cognitive status.
• If the subject is incapable of giving informed consent, the caregiver may consent on behalf of the subject (subject must still confirm assent).
• Subjects with free Trisomy 21.
• Male or female subjects who are 40 and older years of age.
• Subjects who are diagnosed with possible or probable using NINCDS-ADRDA criteria.
• Subjects who live with or have regular visits from a responsible caregiver willing to provide information about the subject's cognitive status.
• If the subject is incapable of giving informed consent, the caregiver may consent on behalf of the subject (subject must still confirm assent).
• Cognitively normal, non-DS individuals.
• Age-matched to the DS group.
• Subjects who signed an Institutional Review Board-approved informed consent.

You may not qualify if:

• Previous or current diagnosis of a neurodegenerative disorders other than AD or DS, including, but not limited to Parkinson's disease, Pick's disease, fronto-temporal dementia, Huntington's chorea, Creutzfeldt-Jacob disease, normal pressure hydrocephalus, and progressive supranuclear palsy.
• Previous or current diagnosis of other dementing/neurodegenerative disease (e.g. Parkinson's disease dementia, dementia with Lewy bodies, Lewy body variant AD).
• Previous or current diagnosis of mixed dementia.
• Previous or current diagnosis of cognitive impairment resulting from other known etiology.
• Previous or current diagnosis of clinically significant infarct or possible multi-infarct dementia as defined by the National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neuroscience (NINDS-AIREN) criteria.
• Previous or current clinically significant psychiatric disease, as judged by Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria, particularly current major depression or schizophrenia. Patients with dementia who are experiencing behavioral disturbances that may require treatment with psychotropic medications may be entered only after discussion and with the approval of the principal investigator. The investigators should carefully consider whether subjects with behavioral dysfunction will be able to complete the imaging session.
• Previous or current history of epilepsy or convulsions, except for febrile convulsions during childhood.
• Current clinically significant hepatic, renal, pulmonary, metabolic, or endocrine disturbances.
• Current clinically significant cardiovascular disease. Clinically significant cardiovascular disease usually includes one or more of the following: a) cardiac surgery or myocardial infarction within the last 6 months; b) unstable angina; c) coronary artery disease that required an increase in medication within the last 3 months; d) decompensated congestive heart failure; e) significant cardiac arrhythmia or conduction disturbance, particularly those resulting in a trial or ventricular fibrillation, or causing syncope, near syncope, or other alterations in mental status; f) severe mitral or aortic valvular disease; g) uncontrolled high blood pressure; h) congenital heart disease) .
• Current history of drug or alcohol abuse within the last year, or prior prolonged history of abuse.
• Current clinically significant infectious disease, including known Acquired Immune Deficiency Syndrome (AIDS) or Human Immunodeficiency Virus (HIV) infection or previous positive test for hepatitis.
• Women of childbearing potential who are not surgically sterile, not refraining from sexual activity, or not using reliable methods of contraception. Women of childbearing potential must not be pregnant (negative serum beta-hCG \[human chorionic gonadotropin\] at the time of screening and negative urine beta-hCG on the day of imaging) or lactating at screening. Women must avoid becoming pregnant, and must agree to refrain from sexual activity or to use reliable contraceptive methods for 30 days prior to and 30 days after administration of radiopharmaceutical imaging agents in this study. In order to participate in this study, sexually active females must be either: two or more years post-menopausal or surgically sterilized, or must be using an acceptable form of contraception (oral contraceptives for at least three months or an IUD (intrauterine device) for at least two months prior to the start of the screening visit, or various barrier methods, e.g., diaphragm or combination condom and spermicide).
• Subjects who, in the opinion of the research team, are otherwise unsuitable for a study of this type.
• Subjects who have a history of relevant severe drug allergy or hypersensitivity.
• Subjects who have received an investigational medication within the last 30 days. Additionally, the time between the last dose of the previous experimental medication and enrollment (completion of screening assessments) must be at least equal to 5 times the terminal half-life of the previous experimental medication.

Sponsors & Collaborators

• St. Joseph's Hospital and Medical Center, Phoenix: lead
• Banner Alzheimer's Institute, Phoenix: collaborator
• Translational Genomics Research Institute (TGEN), Phoenix: collaborator

Study Sites (1)

St. Joseph's Hospital and Medical Center

Phoenix, Arizona, 85013, United States

Location

MeSH Terms

Conditions

Down Syndrome; Alzheimer Disease

Interventions

Fluorodeoxyglucose F18; Actigraphy

Condition Hierarchy (Ancestors)

Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Dementia; Brain Diseases; Central Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Deoxyglucose; Deoxy Sugars; Carbohydrates; Monitoring, Physiologic; Diagnostic Techniques and Procedures; Diagnosis; Accelerometry; Investigative Techniques

Study Officials

• Marwan N Sabbagh, MD

  Barrow Neurological Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Research Clinician

Study Record Dates

• First Submitted: April 15, 2016
• First Posted: May 3, 2016
• Study Start: November 1, 2016
• Primary Completion: December 1, 2018
• Study Completion: December 1, 2018
• Last Updated: October 29, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)