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Evaluating the association between brain atrophy, hypometabolism, and cognitive decline in Alzheimer's disease: a PET/MRI study.

ABSTRACT: Glucose metabolism reduction and brain volume losses are widely reported in Alzheimer's disease (AD). Considering that neuroimaging changes in the hippocampus and default mode network (DMN) are promising important candidate biomarkers and have been included in the research criteria for the diagnosis of AD, it is hypothesized that atrophy and metabolic changes of the abovementioned regions could be evaluated concurrently to fully explore the neural mechanisms underlying cognitive impairment in AD. Twenty-three AD patients and Twenty-four age-, sex- and education level-matched normal controls underwent a clinical interview, a detailed neuropsychological assessment and a simultaneous 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET)/high-resolution T1-weighted magnetic resonance imaging (MRI) scan on a hybrid GE SIGNA PET/MR scanner. Brain volume and glucose metabolism were examined in patients and controls to reveal group differences. Multiple linear regression models were employed to explore the relationship between multiple imaging features and cognitive performance in AD. The AD group had significantly reduced volume in the hippocampus and DMN regions (P < 0.001) relative to that of normal controls determined by using ROI analysis. Compared to normal controls, significantly decreased metabolism in the DMN (P < 0.001) was also found in AD patients, which still survived after controlling for gray matter atrophy (P < 0.001). These findings from ROI analysis were further confirmed by whole-brain confirmatory analysis (P < 0.001, FWE-corrected). Finally, multiple linear regression results showed that impairment of multiple cognitive tasks was significantly correlated with the combination of DMN hypometabolism and atrophy in the hippocampus and DMN regions. This study demonstrated that combining functional and structural features can better explain the cognitive decline of AD patients than unimodal FDG or brain volume changes alone. These findings may have important implications for understanding the neural mechanisms of cognitive decline in AD.

SUBMITTER: Chen Y

PROVIDER: S-EPMC7993730 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCrucial to the success of clinical trials targeting early Alzheimer's disease (AD) is recruiting participants who are more likely to progress over the course of the trials. We hypothesize that a combination of plasma and structural MRI biomarkers, which are less costly and non-invasive, is predictive of longitudinal progression measured by atrophy and cognitive decline in early AD, providing a practical alternative to PET or cerebrospinal fluid biomarkers.MethodsLongitudinal T1-weighted MRI, cognitive (memory-related test scores and clinical dementia rating scale), and plasma measurements of 245 cognitively normal (CN) and 361 mild cognitive impairment (MCI) patients from ADNI were included. Subjects were further divided into β-amyloid positive/negative (Aβ+/Aβ-)] subgroups. Baseline plasma (p-tau181 and neurofilament light chain) and MRI-based structural medial temporal lobe subregional measurements and their association with longitudinal measures of atrophy and cognitive decline were tested using stepwise linear mixed effect modeling in CN and MCI, as well as separately in the Aβ+/Aβ- subgroups. Receiver operating characteristic (ROC) analyses were performed to investigate the discriminative power of each model in separating fast and slow progressors (first and last terciles) of each longitudinal measurement.ResultsA total of 245 CN (35.0% Aβ+) and 361 MCI (53.2% Aβ+) participants were included. In the CN and MCI groups, both baseline plasma and structural MRI biomarkers were included in most models. These relationships were maintained when limited to the Aβ+ and Aβ- subgroups, including Aβ- CN (normal aging). ROC analyses demonstrated reliable discriminative power in identifying fast from slow progressors in MCI [area under the curve (AUC): 0.78-0.93] and more modestly in CN (0.65-0.73).ConclusionsThe present data support the notion that plasma and MRI biomarkers, which are relatively easy to obtain, provide a prediction for the rate of future cognitive and neurodegenerative progression that may be particularly useful in clinical trial stratification and prognosis. Additionally, the effect in Aβ- CN indicates the potential use of these biomarkers in predicting a normal age-related decline.

Project description:Alzheimer's disease is a heterogeneous disorder. Understanding the biological basis for this heterogeneity is key for developing personalized medicine. We identified atrophy subtypes in Alzheimer's disease dementia and tested whether these subtypes are already present in prodromal Alzheimer's disease and could explain interindividual differences in cognitive decline. First we retrospectively identified atrophy subtypes from structural MRI with a data-driven cluster analysis in three datasets of patients with Alzheimer's disease dementia: discovery data (dataset 1: n = 299, age = 67 ± 8, 50% female), and two independent external validation datasets (dataset 2: n = 181, age = 66 ± 7, 52% female; dataset 3: n = 227, age = 74 ± 8, 44% female). Subtypes were compared on clinical, cognitive and biological characteristics. Next, we classified prodromal Alzheimer's disease participants (n = 603, age = 72 ± 8, 43% female) according to the best matching subtype to their atrophy pattern, and we tested whether subtypes showed cognitive decline in specific domains. In all Alzheimer's disease dementia datasets we consistently identified four atrophy subtypes: (i) medial-temporal predominant atrophy with worst memory and language function, older age, lowest CSF tau levels and highest amount of vascular lesions; (ii) parieto-occipital atrophy with poor executive/attention and visuospatial functioning and high CSF tau; (iii) mild atrophy with best cognitive performance, young age, but highest CSF tau levels; and (iv) diffuse cortical atrophy with intermediate clinical, cognitive and biological features. Prodromal Alzheimer's disease participants classified into one of these subtypes showed similar subtype characteristics at baseline as Alzheimer's disease dementia subtypes. Compared across subtypes in prodromal Alzheimer's disease, the medial-temporal subtype showed fastest decline in memory and language over time; the parieto-occipital subtype declined fastest on executive/attention domain; the diffuse subtype in visuospatial functioning; and the mild subtype showed intermediate decline in all domains. Robust atrophy subtypes exist in Alzheimer's disease with distinct clinical and biological disease expression. Here we observe that these subtypes can already be detected in prodromal Alzheimer's disease, and that these may inform on expected trajectories of cognitive decline.

Project description:The mechanisms underlying intracerebral hemorrhage (ICH)-related cognitive impairment (CI) remain unclear. Long-term structural and functional changes were investigated in the brains of healthy male and female Wistar rats after experimental ICH. Following double injection of autologous blood, rats underwent short-term (onset, 3 and 7 days) and long-term (3 and 6 months) radiological assessment and behavioral tests exploring spontaneous locomotion, anxiety-like behavior and working memory, spatial recognition memory and visual recognition memory. Volumetric and metabolic changes in brain areas were examined by 7Tesla-MRI and [18F] FDG-PET, respectively. Brain connectomic disorders and maladaptive processes were seeked through brain metabolic connectivity analysis and atrophy-related network analysis. From an initial hematoma mean volume of 23.35 ± 9.50 mm3, we found early spontaneous locomotor recovery and significant spontaneous blood resorption (≈ 40% of the initial lesion) from days 0 to 7. After 3 and 6 months, ICH rats exhibited CI in several domains as compared to the sham group (working memory: 58.1 ± 1.2 vs. 70.7 ± 1.2%, p < 0.001; spatial recognition memory: 48.7 ± 1.9 vs. 64 ± 1.8%, p < 0.001 and visual recognition memory: 0.14 ± 0.05 vs. 0.33 ± 0.04, p = 0.013, in female only). Rats that experienced ICH had remote and concomitant cerebral atrophy and hypometabolism of ipsilateral striatum, thalamus, limbic system and cortical areas (temporal and parietal lobes). Interestingly, both structural and metabolic deterioration was found in the limbic system connected to the affected site, but remotely from the initial insult. On the other hand, increased activity and functional connectivity occurred in the contralateral hemisphere. These connectomics results showed that both maladaptative and compensation processes coexist in the rat brain following ICH, even at young age and in a disease-free setting. These radiological findings deepen our understanding of ICH-related CI and may serve as biomarkers in the view of future therapeutic intervention.

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Evaluating the association between brain atrophy, hypometabolism, and cognitive decline in Alzheimer's disease: a PET/MRI study.

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