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Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease.

ABSTRACT: Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.

SUBMITTER: Benzinger TL

PROVIDER: S-EPMC3839740 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease.

Benzinger Tammie L S TL Blazey Tyler T Jack Clifford R CR Koeppe Robert A RA Su Yi Y Xiong Chengjie C Raichle Marcus E ME Snyder Abraham Z AZ Ances Beau M BM Bateman Randall J RJ Cairns Nigel J NJ Fagan Anne M AM Goate Alison A Marcus Daniel S DS Aisen Paul S PS Christensen Jon J JJ Ercole Lindsay L Hornbeck Russ C RC Farrar Angela M AM Aldea Patricia P Jasielec Mateusz S MS Owen Christopher J CJ Xie Xianyun X Mayeux Richard R Brickman Adam A McDade Eric E Klunk William W Mathis Chester A CA Ringman John J Thompson Paul M PM Ghetti Bernardino B Saykin Andrew J AJ Sperling Reisa A RA Johnson Keith A KA Salloway Stephen S Correia Stephen S Schofield Peter R PR Masters Colin L CL Rowe Christopher C Villemagne Victor L VL Martins Ralph R Ourselin Sebastien S Rossor Martin N MN Fox Nick C NC Cash David M DM Weiner Michael W MW Holtzman David M DM Buckles Virginia D VD Moulder Krista K Morris John C JC

Proceedings of the National Academy of Sciences of the United States of America 20131105 47

Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging mo ...[more]

PMID: 24194552

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Project description:Tauopathy is a hallmark pathology of Alzheimer's disease with a strong relationship with cognitive impairment. As such, understanding tau may be a key to clinical interventions. In vivo tauopathy has been measured using cerebrospinal fluid assays, but these do not provide information about where pathology is in the brain. The introduction of PET ligands that bind to paired helical filaments provides the ability to measure the amount and distribution of tau pathology. The heritability of the age of dementia onset tied to the specific mutations found in autosomal dominant Alzheimer's disease families provides an elegant model to study the spread of tau across the course of the disease as well as the cross-modal relationship between tau and other biomarkers. To better understand the pathobiology of Alzheimer's disease we measured levels of tau PET binding in individuals with dominantly inherited Alzheimer's disease using data from the Dominantly Inherited Alzheimer Network (DIAN). We examined cross-sectional measures of amyloid-β, tau, glucose metabolism, and grey matter degeneration in 15 cognitively normal mutation non-carriers, 20 asymptomatic carriers, and 15 symptomatic mutation carriers. Linear models examined the association of pathology with group, estimated years to symptom onset, as well as cross-modal relationships. For comparison, tau PET was acquired on 17 older adults with sporadic, late onset Alzheimer disease. Tau PET binding was starkly elevated in symptomatic DIAN individuals throughout the cortex. The brain areas demonstrating elevated tau PET binding overlapped with those seen in sporadic Alzheimer's disease, but with a greater cortical involvement and greater levels of binding despite similar cognitive impairment. Tau PET binding was elevated in the temporal lobe, but the most prominent loci of pathology were in the precuneus and lateral parietal regions. Symptomatic mutation carriers also demonstrated elevated tau PET binding in the basal ganglia, consistent with prior work with amyloid-β. The degree of tau tracer binding in symptomatic individuals was correlated to other biomarkers, particularly markers of neurodegeneration. In addition to the differences seen with tau, amyloid-β was increased in both asymptomatic and symptomatic groups relative to non-carriers. Glucose metabolism showed decline primarily in the symptomatic group. MRI indicated structural degeneration in both asymptomatic and symptomatic cohorts. We demonstrate that tau PET binding is elevated in symptomatic individuals with dominantly inherited Alzheimer's disease. Tau PET uptake was tied to the onset of cognitive dysfunction, and there was a higher amount, and different regional pattern of binding compared to late onset, non-familial Alzheimer's disease.

Project description:Recently, imaging biomarkers have gained importance for the characterization of patients with Alzheimer's disease; however, the relationship between regional biomarker expression and cognitive function remains unclear. In our study, we investigated associations between scores on CERAD neuropsychological assessment battery (CERAD-NAB) subtests with regional glucose metabolism, cortical thickness and amyloid deposition in patients with early Alzheimer's disease (AD) using [18F]-fluorodeoxyglucose (FDG), structural MRI, and 11C-Pittsburgh Compound B (PiB) positron emission tomography (PET), respectively. A total of 76 patients (mean age 68.4 ± 8.5 years, 57.9% male) with early AD (median global clinical dementia rating (CDR) score = 0.5, range: 0.5-2.0) were studied. Associations were investigated by correlation and multiple regression analyses. Scores on cognitive subtests were most closely predicted by regional glucose metabolism with explained variance up to a corrected R² of 0.518, followed by cortical thickness and amyloid deposition. Prediction of cognitive subtest performance was increased up to a corrected R² of 0.622 for Word List-Delayed Recall, when biomarker information from multiple regions and multiple modalities were included. For verbal, visuoconstructive and mnestic domains the closest associations with FDG-PET imaging were found in the left lateral temporal lobe, right parietal lobe, and posterior cingulate cortex, respectively. Decreased cortical thickness in parietal regions was most predictive of impaired subtest performance. Remarkably, cerebral amyloid deposition significantly predicted cognitive function in about half of the subtests but with smaller extent of variance explained (corrected R² ? 0.220). We conclude that brain metabolism and atrophy affect cognitive performance in a regionally distinct way. Significant predictions of cognitive function by PiB-PET in half of CERAD-NAB subtests suggest functional relevance even in symptomatic patients with AD, challenging the concept of plateauing cortical amyloid deposition early in the disease course. Our results underscore the complex spatial relationship between different imaging biomarkers.

Dataset Information

Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease.

Publications

Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease.

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