Clinical Correlates of the PET-based Braak Staging Framework in Alzheimer's Disease.

In vivo Alzheimer's disease diagnosis and staging is traditionally based on clinical features. However, the agreement between clinical and pathological Alzheimer's disease diagnosis, whose diagnosis assessment includes amyloid and Braak histopathological tau staging, is not completely convergent. The development of positron emission tomography (PET) tracers targeting neurofibrillary tangles offers prospects for advancing the staging of Alzheimer's disease from both biological and clinical perspectives. Recent advances in radiochemistry made it possible to apply the postmortem Braak staging framework to tau-PET images obtained in vivo. Here, our aim is to provide a narrative review of the current literature on the relationship between Alzheimer's disease clinical features and the PET-based Braak staging framework. Overall, the available studies support the stepwise increase in disease severity following the advance of PET-based Braak stages, with later stages being associated with worse cognitive and clinical symptoms. In line with this, there is a trend for unimpaired cognition, mild cognitive impairment, and Alzheimer's disease dementia to be compatible with early, intermediate, and late patterns of tau deposition based on PET-based Braak stages. Moreover, neuropsychiatric symptom severity seems to be linked to the extent of tau-PET signal across Braak areas. In sum, this framework seems to correspond well with the clinical progression of Alzheimer's disease, which is an indication of its potential utility in research and clinical practice, especially for detecting preclinical tau levels in individuals without symptoms. However, further research is needed to improve the generalizability of these findings and to better understand the applications of this staging framework.

Neuroinflammation Biomarkers in the AT(N) Framework Across the Alzheimer's Disease Continuum.

In the past years, neuroinflammation has been widely investigated in Alzheimer's disease (AD). Evidence from animal, in vivo and post-mortem studies has shown that inflammatory changes are a common feature of the disease, apparently happening in response to amyloid-beta and tau accumulation. Progress in imaging and fluid biomarkers now allows for identifying surrogate markers of neuroinflammation in living individuals, which may offer unprecedented opportunities to better understand AD pathogenesis and progression. In this context, inflammatory mediators and glial proteins (mainly derived from microglial cells and astrocytes) seem to be the most promising biomarkers. Here, we discuss the biological basis of neuroinflammation in AD, revise the proposed neuroinflammation biomarkers, describe what we have learned from anti-inflammatory drug trials, and critically discuss the potential addition of these biomarkers in the AT(N) framework.

Impact of the biological definition of Alzheimer's disease using amyloid, tau and neurodegeneration (ATN): what about the role of vascular changes, inflammation, Lewy body pathology?

BACKGROUND: The NIA-AA research framework proposes a biological definition of Alzheimer's disease, where asymptomatic persons with amyloid deposition would be considered as having this disease prior to symptoms. DISCUSSION: Notwithstanding the fact that amyloid deposition in isolation is not associated with dementia, even the combined association of amyloid and tau pathology does not inevitably need to dementia over age 65. Other pathological factors may play a leading or an accelerating role in age-associated cognitive decline, including vascular small vessel disease, neuroinflammation and Lewy Body pathology. CONCLUSION: Research should aim at understanding the interaction between all these factors, rather than focusing on them individually. Hopefully this will lead to a personalized approach to the prevention of brain aging, based on individual biological, genetic and cognitive profiles.

Amyloid-ß and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer's disease.

This study was designed to test the interaction between amyloid-ß and tau proteins as a determinant of metabolic decline in preclinical Alzheimer's disease (AD). We assessed 120 cognitively normal individuals with [18F]florbetapir positron emission tomography (PET) and cerebrospinal fluid (CSF) measurements at baseline, as well as [18F]fluorodeoxyglucose ([18F]FDG) PET at baseline and at 24 months. A voxel-based interaction model was built to test the associations between continuous measurements of CSF biomarkers, [18F]florbetapir and [18F]FDG standardized uptake value ratios (SUVR). We found that the synergistic interaction between [18F]florbetapir SUVR and CSF phosphorylated tau (p-tau) measurements, rather than the sum of their independent effects, was associated with a 24-month metabolic decline in basal and mesial temporal, orbitofrontal, and anterior and posterior cingulate cortices (P<0.001). In contrast, interactions using CSF amyloid-ß1-42 and total tau biomarkers did not associate with metabolic decline over a time frame of 24 months. The interaction found in this study further support the framework that amyloid-ß and hyperphosphorylated tau aggregates synergistically interact to cause downstream AD neurodegeneration. In fact, the regions displaying the metabolic decline reported here were confined to brain networks affected early by amyloid-ß plaques and neurofibrillary tangles. Preventive clinical trials may benefit from using a combination of amyloid-ß PET and p-tau biomarkers to enrich study populations of cognitively normal subjects with a high probability of disease progression in studies, using [18F]FDG as a biomarker of efficacy.