ABSTRACT
Background: The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood. Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau, and p-tau181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits. Results: Aß1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Aß1-40 was heritable. No significant linkage (LOD > 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome-wide association identified a suggestive locus near the chromosome 4 linkage peak. Conclusions: Overall, these results support the vervet as a non-human primate model of amyloid-related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Aß1-40 and p-tau181 as potentially valuable biomarkers of these processes.
Subject(s)
Aging , Amyloid beta-Peptides , Brain/pathology , Cerebral Amyloid Angiopathy , Chlorocebus aethiops , Monkey Diseases , Peptide Fragments , tau Proteins , Aging/cerebrospinal fluid , Aging/genetics , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Amyloid beta-Peptides/genetics , Animals , Biomarkers/cerebrospinal fluid , Cerebral Amyloid Angiopathy/cerebrospinal fluid , Cerebral Amyloid Angiopathy/genetics , Chromosomes, Mammalian , Female , Genetic Linkage , Genome-Wide Association Study , Male , Models, Animal , Monkey Diseases/cerebrospinal fluid , Monkey Diseases/genetics , Neurodegenerative Diseases/cerebrospinal fluid , Neurodegenerative Diseases/genetics , Neuroimaging/methods , Organ Size , Pedigree , Peptide Fragments/cerebrospinal fluid , Peptide Fragments/genetics , tau Proteins/cerebrospinal fluid , tau Proteins/geneticsABSTRACT
OBJECTIVES: To determine the neuropathological load in the living brain of nondemented adults with Down syndrome using positron emission tomography with 2-(1-{6-[(2-fluorine 18-labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([(18)F]FDDNP) and to assess the influence of age and cognitive and behavioral functioning. For reference, [(18)F]FDDNP binding values and patterns were compared with those from patients with Alzheimer disease and cognitively intact control participants. DESIGN: Cross-sectional clinical study. PARTICIPANTS: Volunteer sample of 19 persons with Down syndrome without dementia (mean age, 36.7 years), 10 patients with Alzheimer disease (mean age, 66.5 years), and 10 controls (mean age, 43.8 years). MAIN OUTCOME MEASURES: Binding of [(18)F]FDDNP in brain regions of interest, including the parietal, medial temporal, lateral temporal, and frontal lobes and posterior cingulate gyrus, and the average of all regions (global binding). RESULTS: The [(18)F]FDDNP binding values were higher in all brain regions in the Down syndrome group than in controls. Compared with the Alzheimer disease group, the Down syndrome group had higher [(18)F]FDDNP binding values in the parietal and frontal regions, whereas binding levels in other regions were comparable. Within the Down syndrome group, age correlated with [(18)F]FDDNP binding values in all regions except the posterior cingulate, and several measures of behavioral dysfunction showed positive correlations with global, frontal, parietal, and posterior cingulate [(18)F]FDDNP binding. CONCLUSIONS: Consistent with neuropathological findings from postmortem studies, [(18)F]FDDNP positron emission tomography shows high binding levels in Down syndrome comparable to Alzheimer disease and greater levels than in members of a control group. The positive associations between [(18)F]FDDNP binding levels and age as well as behavioral dysfunction in Down syndrome are consistent with the age-related progression of Alzheimer-type neuropathological findings in this population.
Subject(s)
Amyloid beta-Peptides/metabolism , Down Syndrome/metabolism , Down Syndrome/pathology , tau Proteins/metabolism , Adult , Aged , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Cross-Sectional Studies , Down Syndrome/diagnostic imaging , Female , Humans , Male , Middle Aged , Plaque, Amyloid/diagnostic imaging , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Positron-Emission Tomography/methods , Protein Binding , Young AdultABSTRACT
Measures developed from animal models of aging may detect dementia of the Alzheimer's type in a population at-risk for Alzheimer's disease (AD). Although, by middle age, individuals with Down syndrome (DS) show an extraordinarily high prevalence of AD-type pathology, their severe idiopathic cognitive deficits tend to confound the clinical diagnosis of AD. The current study was designed to improve detection of AD in DS by using measures of learning and memory derived from animal models of aging. Adults with DS (N=34) were assessed and reassessed (n=19) approximately one year later using stimulus-response (S-R) test methods derived from experimental literature, as well as standardized informant-based tests. Results demonstrated high validity and reliability of select tests. The implication of early symptom detection in a population at-risk for AD-type dementia was discussed in terms of potential brain regions of interest.
