An investigation of the role of brain amyloid in cognition, brain atrophy and Alzheimer s disease in Down s syndrome
Lead Research Organisation:
University of Cambridge
Department Name: Psychiatry
Abstract
In the UK there are about 60,000 people with Down s syndrome (DS). Like the general population, people with DS are living longer. As a group they have the highest age-related risk for developing dementia due to Alzheimer?s disease (AD) at a relatively young age - 50% of people with DS develop AD by the age of 59 years (compared to less than 1% of the general population). This places a great burden on individuals, families and society.
We do not know what causes AD but there is evidence that an excess deposition of a protein called beta-amyloid in the brain is a culprit early in the disease process resulting in a cascade of effects on the brain and in brain-cell death (observed in AD) and dementia. People with DS produce beta-amyloid in excess as they are born with an extra copy of the gene coding for the precursor of beta-amyloid. Post-mortem studies of brain tissue from people with DS have revealed that beta-amyloid is widely present at a very young age and is found in all who are in their forties or older.
A recently developed method for detecting beta-amyloid deposition using PET (positron emission tomography) brain scanning technology together with a beta-amyloid tracer (Pittsburgh Compound-B) can safely and reliably measure the amount and distribution of beta-amyloid in the brain during life. Studies have been done in AD affecting the general population but none in people with DS.
We have completed a pilot study using this technique and found that it was acceptable to people with DS, and it can detect beta-amyloid in their brains. We are now proposing a clinical study with 60 participants using this technique to help us answer questions about the effect that excess beta-amyloid has on the brain and on mental (or cognitive) functioning (e.g. memory), and the risk of dementia. Together with the use of specific cognitive assessments, we will scan people with DS once at the start and again after two years. We will investigate the relationship between cerebral amyloid deposition, brain atrophy and cognitive decline and dementia. New potentially preventative treatments are being developed for AD that target amyloid turnover in the brain. This study will inform such developments and people with DS may be the first to benefit if they are safe and effective. Observations in people with DS may also inform treatments of AD in the general population.
We do not know what causes AD but there is evidence that an excess deposition of a protein called beta-amyloid in the brain is a culprit early in the disease process resulting in a cascade of effects on the brain and in brain-cell death (observed in AD) and dementia. People with DS produce beta-amyloid in excess as they are born with an extra copy of the gene coding for the precursor of beta-amyloid. Post-mortem studies of brain tissue from people with DS have revealed that beta-amyloid is widely present at a very young age and is found in all who are in their forties or older.
A recently developed method for detecting beta-amyloid deposition using PET (positron emission tomography) brain scanning technology together with a beta-amyloid tracer (Pittsburgh Compound-B) can safely and reliably measure the amount and distribution of beta-amyloid in the brain during life. Studies have been done in AD affecting the general population but none in people with DS.
We have completed a pilot study using this technique and found that it was acceptable to people with DS, and it can detect beta-amyloid in their brains. We are now proposing a clinical study with 60 participants using this technique to help us answer questions about the effect that excess beta-amyloid has on the brain and on mental (or cognitive) functioning (e.g. memory), and the risk of dementia. Together with the use of specific cognitive assessments, we will scan people with DS once at the start and again after two years. We will investigate the relationship between cerebral amyloid deposition, brain atrophy and cognitive decline and dementia. New potentially preventative treatments are being developed for AD that target amyloid turnover in the brain. This study will inform such developments and people with DS may be the first to benefit if they are safe and effective. Observations in people with DS may also inform treatments of AD in the general population.
Technical Summary
Adults with Down?s syndrome (DS) are at high risk for developing Alzheimer s disease (AD) early in life. The extra-copy of the Amyloid Precursor Protein gene due to trisomy 21 leads to an increase in beta-amyloid production. It is widely accepted that beta-amyloid plays a central role in the pathogenesis of AD, but the nature of this is not fully understood. The study of AD in DS enables investigation of beta-amyloid and its impact on cerebral atrophy, cognition and dementia thereby informing the development of preventative therapies specifically those targeting cerebral amyloid turnover.
A new technique that enables the in vivo measurement of cerebral deposition of beta-amyloid using Pittsburgh Compound-B (11C-PiB) with positron emission tomography (PET) has been extensively used in the study of sporadic AD, but not in DS. We have successfully completed a pilot study that has demonstrated that the technique is feasible and acceptable to people with DS and that beta-amyloid can be detected. We are now proposing a clinical study to measure cerebral beta-amyloid in vivo in adults with DS at different stages (pre-diagnosis and diagnosis stages) of AD. Using cross-sectional and longitudinal designs, dynamic 11C-PiB-PET-MRI scanning, MRI voxel-based measures of regional cerebral morphology, and diffusion tensor MRI to evaluate white matter pathways, our aims are to investigate the relationship between cerebral beta-amyloid distribution and load in people with DS in vivo with the following:
? Regional and generalised cerebral atrophy and white matter pathway integrity;
? Specific cognitive deficits
? Clinical evidence of: a) the pre-dementia state (defined as the ?frontal-like? dementia of DS), and b) AD.
In this four-year study we will recruit 60 participants with DS between 35 and 55 years of age with mild to moderate degree of intellectual disability, where 30 will have no evidence of AD, 10 will have clinical evidence of AD and 20 will have symptoms suggestive of a pre-dementia state for AD. All will have full diagnostic and neuropsychological assessments specifically developed to assess dementia in people with intellectual disabilities and the above scans at the beginning of the study. In the second stage, we will re-scan two age-matched groups with DS without dementia divided based on being amyloid positive or negative to investigate cerebral and clinical change over time. Between and within participant analyses will be used to establish the relationship between cerebral amyloid deposition, atrophy, white matter tract integrity and clinical status.
A new technique that enables the in vivo measurement of cerebral deposition of beta-amyloid using Pittsburgh Compound-B (11C-PiB) with positron emission tomography (PET) has been extensively used in the study of sporadic AD, but not in DS. We have successfully completed a pilot study that has demonstrated that the technique is feasible and acceptable to people with DS and that beta-amyloid can be detected. We are now proposing a clinical study to measure cerebral beta-amyloid in vivo in adults with DS at different stages (pre-diagnosis and diagnosis stages) of AD. Using cross-sectional and longitudinal designs, dynamic 11C-PiB-PET-MRI scanning, MRI voxel-based measures of regional cerebral morphology, and diffusion tensor MRI to evaluate white matter pathways, our aims are to investigate the relationship between cerebral beta-amyloid distribution and load in people with DS in vivo with the following:
? Regional and generalised cerebral atrophy and white matter pathway integrity;
? Specific cognitive deficits
? Clinical evidence of: a) the pre-dementia state (defined as the ?frontal-like? dementia of DS), and b) AD.
In this four-year study we will recruit 60 participants with DS between 35 and 55 years of age with mild to moderate degree of intellectual disability, where 30 will have no evidence of AD, 10 will have clinical evidence of AD and 20 will have symptoms suggestive of a pre-dementia state for AD. All will have full diagnostic and neuropsychological assessments specifically developed to assess dementia in people with intellectual disabilities and the above scans at the beginning of the study. In the second stage, we will re-scan two age-matched groups with DS without dementia divided based on being amyloid positive or negative to investigate cerebral and clinical change over time. Between and within participant analyses will be used to establish the relationship between cerebral amyloid deposition, atrophy, white matter tract integrity and clinical status.