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Emerging ?-amyloid pathology and accelerated cortical atrophy.

ABSTRACT: The effect of ?-amyloid (A?) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood.To test the hypothesis that the development of A? pathology is related to increased regional atrophy in the brains of cognitively normal (CN) persons.Longitudinal clinicobiomarker cohort study involving 47 CN control subjects and 15 patients with AD dementia. All participants underwent repeated cerebrospinal fluid A?42 and structural magnetic resonance imaging measurements for up to 4 years. Cognitively normal controls were classified using the longitudinal cerebrospinal fluid A?42 data and included 13 stable A? negative (normal baseline A?42 levels, with less than the median reduction over time), 13 declining A? negative (normal baseline A?42 levels, with greater than the median reduction over time), and 21 A? positive (pathologic baseline A?42 levels). All 15 patients with AD dementia were A? positive.Group effects on regional gray matter volumes at baseline and over time, tested by linear mixed-effects models.Baseline gray matter volumes were similar among the CN A? groups, but atrophy rates were increased in frontoparietal regions in the declining A?-negative and A?-positive groups and in amygdala and temporal regions in the A?-positive group. A?-positive patients with AD dementia had further increased atrophy rates in hippocampus and temporal and cingulate regions.Emerging A? pathology is coupled to increased frontoparietal (but not temporal) atrophy rates. Atrophy rates peak early in frontoparietal regions but accelerate in hippocampus, temporal, and cingulate regions as the disease progresses to dementia. Early-stage A? pathology may have mild effects on local frontoparietal cortical integrity while effects in temporal regions appear later and accelerate, leading to the atrophy pattern typically seen in AD.

SUBMITTER: Mattsson N

PROVIDER: S-EPMC4410966 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Emerging β-amyloid pathology and accelerated cortical atrophy.

Mattsson Niklas N Insel Philip S PS Nosheny Rachel R Tosun Duygu D Trojanowski John Q JQ Shaw Leslie M LM Jack Clifford R CR Donohue Michael C MC Weiner Michael W MW

JAMA neurology 20140601 6

<h4>Importance</h4>The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood.<h4>Objective</h4>To test the hypothesis that the development of Aβ pathology is related to increased regional atrophy in the brains of cognitively normal (CN) persons.<h4>Design, setting, and participants</h4>Longitudinal clinicobiomarker cohort study involving 47 CN control subjects and 15 patients with AD dementia. All participants ...[more]

PMID: 24781145

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Project description:BackgroundCortical atrophy is associated with cognitive decline, but the association is not perfect. We aimed to identify factors explaining the discrepancy between the degree of cortical atrophy and cognitive decline in cognitively unimpaired elderly.MethodsThe discrepancy between atrophy and cognitive decline was measured using the residuals from a linear regression analysis between change in whole brain cortical thickness over time and change in a cognitive composite measure over time in 395 cognitively unimpaired participants from the Swedish BioFINDER study. We tested for bivariate associations of this residual measure with demographic, imaging, and fluid biomarker variables using Pearson correlations and independent-samples t-tests, and for multivariate associations using linear regression models. Mediation analyses were performed to explore possible paths between the included variables.ResultsIn bivariate analyses, older age (r = -0.11, p = 0.029), male sex (t = -3.00, p = 0.003), larger intracranial volume (r = -0.17, p < 0.001), carrying an APOEe4 allele (t = -2.71, p = 0.007), larger white matter lesion volume (r = -0.16, p = 0.002), lower cerebrospinal fluid (CSF) β-amyloid (Aβ) 42/40 ratio (t = -4.05, p < 0.001), and higher CSF levels of phosphorylated tau (p-tau) 181 (r = -0.22, p < 0.001), glial fibrillary acidic protein (GFAP; r = -0.15, p = 0.003), and neurofilament light (NfL; r = -0.34, p < 0.001) were negatively associated with the residual measure, i.e., associated with worse than expected cognitive trajectory given the level of atrophy. In a multivariate analysis, only lower CSF Aβ42/40 ratio and higher CSF NfL levels explained cognition beyond brain atrophy. Mediation analyses showed that associations between the residual measure and APOEe4 allele, CSF Aβ42/40 ratio, and CSF GFAP and p-tau181 levels were mediated by levels of CSF NfL, as were the associations with the residual measure for age, sex, and WML volume.ConclusionsOur results suggest that axonal degeneration and amyloid pathology independently affect the rate of cognitive decline beyond the degree of cortical atrophy. Furthermore, axonal degeneration mediated the negative effects of old age, male sex, and white matter lesions, and in part also amyloid and tau pathology, on cognition over time when accounting for cortical atrophy.

Project description:IntroductionAlzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) associated with brain atrophy and cognitive decline. The functional form to model the association between Aβ and regional brain atrophy has not been well defined. To determine the relationship between Aβ and atrophy, we compared the performance of the usual dichotomization of cerebrospinal fluid (CSF) Aβ to identify subjects as Aβ+ and Aβ- with a trilinear spline model of CSF Aβ.MethodsOne hundred and eighty-three subjects with mild cognitive impairment and 108 cognitively normal controls with baseline CSF Aβ and up to 4 years of longitudinal magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative were analyzed using mixed-effects regression. Piecewise-linear splines were used to evaluate the nonlinear nature of the association between CSF Aβ and regional atrophy and to identify points of acceleration of atrophy with respect to Aβ. Several parameterizations of CSF Aβ were compared using likelihood ratio tests and the Akaike information criterion. Periods of acceleration of atrophy in which subjects transition from CSF Aβ negativity to CSF Aβ positivity were estimated from the spline models and tested for significance.ResultsSpline models resulted in better fits for many temporal and parietal regions compared with the dichotomous models. The trilinear model showed that periods of acceleration of atrophy varied greatly by region with early changes seen in the insula, amygdala, precuneus, hippocampus, and other temporal regions, occurring before the clinical threshold for CSF Aβ positivity.DiscussionThe use of piecewise-linear splines provides an improved model of the nonlinear association between CSF Aβ and regional atrophy in regions implicated in the progression of AD. The important biological finding of this work is that some brain regions show periods of accelerated volume loss well before the CSF Aβ42 threshold. This implies that signs of brain atrophy develop before the current conventional definition of "preclinical AD".

Project description:Abstract White matter hyperintensities (WMHs) have a heterogeneous aetiology, associated with both vascular risk factors and amyloidosis due to Alzheimer’s disease. While spatial distribution of both amyloid and WM lesions carry important information for the underlying pathogenic mechanisms, the regional relationship between these two pathologies and their joint contribution to early cognitive deterioration remains largely unexplored. We included 662 non-demented participants from three Amyloid Imaging to Prevent Alzheimer’s disease (AMYPAD)-affiliated cohorts: EPAD-LCS (N = 176), ALFA+ (N = 310), and EMIF-AD PreclinAD Twin60++ (N = 176). Using PET imaging, cortical amyloid burden was assessed regionally within early accumulating regions (medial orbitofrontal, precuneus, and cuneus) and globally, using the Centiloid method. Regional WMH volume was computed using Bayesian Model Selection. Global associations between WMH, amyloid, and cardiovascular risk scores (Framingham and CAIDE) were assessed using linear models. Partial least square (PLS) regression was used to identify regional associations. Models were adjusted for age, sex, and APOE-e4 status. Individual PLS scores were then related to cognitive performance in 4 domains (attention, memory, executive functioning, and language). While no significant global association was found, the PLS model yielded two components of interest. In the first PLS component, a fronto-parietal WMH pattern was associated with medial orbitofrontal–precuneal amyloid, vascular risk, and age. Component 2 showed a posterior WMH pattern associated with precuneus-cuneus amyloid, less related to age or vascular risk. Component 1 was associated with lower performance in all cognitive domains, while component 2 only with worse memory. In a large pre-dementia population, we observed two distinct patterns of regional associations between WMH and amyloid burden, and demonstrated their joint influence on cognitive processes. These two components could reflect the existence of vascular-dependent and -independent manifestations of WMH-amyloid regional association that might be related to distinct primary pathophysiology. Lorenzini et al. describe two distinct regional patterns of association between white matter hyperintensities (WMHs) and early amyloid deposition, differentially related to vascular risk factors and cognitive performance. These results suggest the existence of vascular-dependent and -independent manifestations of WMH-amyloid regional association that might be related to distinct primary pathophysiology. Graphical Abstract Graphical abstract

Project description:Markers of downstream events are a key component of clinical trials of disease-modifying therapies for Alzheimer's disease. Morphological metrics like cortical thickness are established measures of atrophy but are not sensitive enough to detect amyloid-beta (Aβ)- related changes that occur before overt atrophy become visible. We aimed to investigate to what extent diffusion MRI can provide sensitive markers of cortical microstructural changes and to test their associations with multiple aspects of the Alzheimer's disease pathological cascade, including both Aβ and tau accumulation, astrocytic activation and cognitive deficits. We applied the mean apparent diffusion propagator model to diffusion MRI data from 492 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER-2 cohort. Participants were stratified in Aβ-negative/tau-negative, Aβ-positive/tau-negative and Aβ-positive/tau-positive based on Aβ- and tau-PET uptake. Cortical regional values of diffusion MRI metrics and cortical thickness were compared across groups. Associations between regional values of diffusion MRI metrics and both Aβ- and tau-PET uptake were also investigated along with the association with plasma level of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation (available in 292 participants). Mean squared displacement revealed widespread microstructural differences already between Aβ-negative/tau-negative and Aβ-positive/tau-negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation. In contrast, differences in cortical thickness were clearly more limited. Mean squared displacement was also correlated with both Aβ- and tau-PET uptake even independently from one another and from cortical thickness. Further, the same metric exhibited significantly stronger correlations with PET uptake than cortical thickness (P < 0.05). Mean squared displacement was also positively correlated with GFAP with a pattern that resembles Aβ accumulation, and GFAP partially mediated the association between Aβ accumulation and mean squared displacement. Further, impairments in executive functions were significantly more associated with mean squared displacement values extracted from a meta-region of interest encompassing regions accumulating Aβ early in the disease process, than with cortical thickness (P < 0.05). Similarly, impairments in memory functions were significantly more associated with mean squared displacement values extracted from a temporal meta-region of interest than with cortical thickness (P < 0.05). Metrics of cortical microstructural alteration derived from diffusion MRI are highly sensitive to multiple aspects of the Alzheimer's disease pathological cascade. Of particular interest is the link with both Aβ-PET and GFAP, suggesting diffusion MRI might reflects microstructural changes related to the astrocytic response to Aβ aggregation. Therefore, metrics of cortical diffusion might be important outcome measures in anti-Aβ treatments clinical trials for detecting drug-induced changes in cortical microstructure.

Project description:Heterogeneity within the Alzheimer's disease (AD) syndromic spectrum is typically classified in a domain-specific manner (e.g., language vs. visual cognitive function). The central aim of this study was to investigate whether impairment in visual cognitive tasks thought to be subserved by posterior cortical dysfunction in non-amnestic AD presentations is associated with tau, amyloid, or neurodegeneration in those regions using 18F-AV-1451 and 11C-PiB positron emission tomography (PET) and magnetic resonance imaging (MRI). Sixteen amyloid-positive patients who met criteria for either Posterior Cortical Atrophy (PCA; n = 10) or logopenic variant Primary Progressive Aphasia (lvPPA; n = 6) were studied. All participants underwent a structured clinical assessment, neuropsychological battery, structural MRI, amyloid PET, and tau PET. The neuropsychological battery included two visual cognitive tests: VOSP Number Location and Benton Facial Recognition. Surface-based whole-cortical general linear models were used to first explore the similarities and differences between these biomarkers in the two patient groups, and then to assess their regional associations with visual cognitive test performance. The results show that these two variants of AD have both dissociable and overlapping areas of tau and atrophy, but amyloid is distributed with a stereotyped localization in both variants. Performance on both visual cognitive tests were associated with tau and atrophy in the right lateral and medial occipital association cortex, superior parietal cortex, and posterior ventral occipitotemporal cortex. No cortical associations were observed with amyloid PET. We further demonstrate that cortical atrophy has a partially mediating effect on the association between tau pathology and visual cognitive task performance. Our findings show that non-amnestic variants of AD have partially dissociable spatial patterns of tau and atrophy that localize as expected based on symptoms, but similar patterns of amyloid. Further, we demonstrate that impairments of visual cognitive dysfunction are strongly associated with tau in visual cortical regions and mediated in part by atrophy.

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Emerging ?-amyloid pathology and accelerated cortical atrophy.

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Emerging β-amyloid pathology and accelerated cortical atrophy.

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