Tau Aggregation Correlates with Amyloid Deposition in Both Mild Cognitive Impairment and Alzheimer's Disease Subjects.

BACKGROUND: Amyloid plaque and tau-containing neurofibrillary tangles are important features of Alzheimer's disease (AD). However, the relationship between these processes is still debated. OBJECTIVE: We aimed to investigate local and distant relationships between tau and amyloid deposition in the cortex in mild cognitive impairment (MCI) and AD using PET imaging. METHODS: Seventy-nine subjects (51 controls, 13 amyloid-positive MCI subjects, and 15 amyloid positive AD subjects) underwent MRI and 18F-flutemetamol PET. All MCI/AD subjects and 8 healthy controls as well as 33 healthy control subjects from the ADNI dataset also had 18F-AV1451 PET. Regional and distant correlations were examined after sampling target-to-cerebellar ratio images. Biological parametric mapping was used to evaluate voxel level correlations locally. RESULTS: We found multiple clusters of voxels with highly significant positive correlations throughout the association cortex in both MCI and AD subjects. CONCLUSION: The multiple clusters of positive correlations indicate that tau and amyloid may interact locally and be involved in disease progression. Our findings suggest that targeting both pathologies may be required.

Microglial activation correlates in vivo with both tau and amyloid in Alzheimer's disease.

Alzheimer's disease is characterized by the histopathological presence of amyloid-ß plaques and tau-containing neurofibrillary tangles. Microglial activation is also a recognized pathological component. The relationship between microglial activation and protein aggregation is still debated. We investigated the relationship between amyloid plaques, tau tangles and activated microglia using PET imaging. Fifty-one subjects (19 healthy controls, 16 mild cognitive impairment and 16 Alzheimer's disease subjects) participated in the study. All subjects had neuropsychometric testing, MRI, amyloid (18F-flutemetamol), and microglial (11C-PBR28) PET. All subjects with mild cognitive impairment and Alzheimer's disease and eight of the controls had tau (18F-AV1451) PET. 11C-PBR28 PET was analysed using Logan graphical analysis with an arterial plasma input function, while 18F-flutemetamol and 18F-AV1451 PET were analysed as target:cerebellar ratios to create parametric standardized uptake value ratio maps. Biological parametric mapping in the Statistical Parametric Mapping platform was used to examine correlations between uptake of tracers at a voxel-level. There were significant widespread clusters of positive correlation between levels of microglial activation and tau aggregation in both the mild cognitive impairment (amyloid-positive and amyloid-negative) and Alzheimer's disease subjects. The correlations were stronger in Alzheimer's disease than in mild cognitive impairment, suggesting that these pathologies increase together as disease progresses. Levels of microglial activation and amyloid deposition were also correlated, although in a different spatial distribution; correlations were stronger in mild cognitive impairment than Alzheimer's subjects, in line with a plateauing of amyloid load with disease progression. Clusters of positive correlations between microglial activation and protein aggregation often targeted similar areas of association cortex, indicating that all three processes are present in specific vulnerable brain areas. For the first time using PET imaging, we show that microglial activation can correlate with both tau aggregation and amyloid deposition. This confirms the complex relationship between these processes. These results suggest that preventative treatment for Alzheimer's disease should target all three processes.

The delirium and population health informatics cohort study protocol: ascertaining the determinants and outcomes from delirium in a whole population.

BACKGROUND: Delirium affects 25% of older inpatients and is associated with long-term cognitive impairment and future dementia. However, no population studies have systematically ascertained cognitive function before, cognitive deficits during, and cognitive impairment after delirium. Therefore, there is a need to address the following question: does delirium, and its features (including severity, duration, and presumed aetiologies), predict long-term cognitive impairment, independent of cognitive impairment at baseline? METHODS: The Delirium and Population Health Informatics Cohort (DELPHIC) study is an observational population-based cohort study based in the London Borough of Camden. It is recruiting 2000 individuals aged ≥70 years and prospectively following them for two years, including daily ascertainment of all inpatient episodes for delirium. Daily inpatient assessments include the Memorial Delirium Assessment Scale, the Observational Scale for Level of Arousal, and the Hierarchical Assessment of Balance and Mobility. Data on delirium aetiology is also collected. The primary outcome is the change in the modified Telephone Interview for Cognitive Status at two years. DISCUSSION: DELPHIC is the first population sample to assess older persons before, during and after hospitalisation. The cumulative incidence of delirium in the general population aged ≥70 will be described. DELPHIC offers the opportunity to quantify the impact of delirium on cognitive and functional outcomes. Overall, DELPHIC will provide a real-time public health observatory whereby information from primary, secondary, intermediate and social care can be integrated to understand how acute illness is linked to health and social care outcomes.