Neuroinflammation is highest in areas of disease progression in semantic dementia.

Despite epidemiological and genetic data linking semantic dementia to inflammation, the topography of neuroinflammation in semantic dementia, also known as the semantic variant of primary progressive aphasia, remains unclear. The pathology starts at the tip of the left temporal lobe where, in addition to cortical atrophy, a strong signal appears with the tau PET tracer 18F-flortaucipir, even though the disease is not typically associated with tau but with TDP-43 protein aggregates. Here, we characterized the topography of inflammation in semantic variant primary progressive aphasia using high-resolution PET and the tracer 11C-PBR28 as a marker of microglial activation. We also tested the hypothesis that inflammation, by providing non-specific binding targets, could explain the 18F-flortaucipir signal in semantic variant primary progressive aphasia. Eight amyloid-PET-negative patients with semantic variant primary progressive aphasia underwent 11C-PBR28 and 18F-flortaucipir PET. Healthy controls underwent 11C-PBR28 PET (n = 12) or 18F-flortaucipir PET (n = 12). Inflammation in PET with 11C-PBR28 was analysed using Logan graphical analysis with a metabolite-corrected arterial input function. 18F-flortaucipir standardized uptake value ratios were calculated using the cerebellum as the reference region. Since monoamine oxidase B receptors are expressed by astrocytes in affected tissue, selegiline was administered to one patient with semantic variant primary progressive aphasia before repeating 18F-flortaucipir scanning to test whether monoamine oxidase B inhibition blocked flortaucipir binding, which it did not. While 11C-PBR28 uptake was mostly cortical, 18F-flortaucipir uptake was greatest in the white matter. The uptake of both tracers was increased in the left temporal lobe and in the right temporal pole, as well as in regions adjoining the left temporal pole such as insula and orbitofrontal cortex. However, peak uptake of 18F-flortaucipir localized to the left temporal pole, the epicentre of pathology, while the peak of inflammation 11C-PBR28 uptake localized to a more posterior, mid-temporal region and left insula and orbitofrontal cortex, in the periphery of the damage core. Neuroinflammation, greatest in the areas of progression of the pathological process in semantic variant primary progressive aphasia, should be further studied as a possible therapeutic target to slow disease progression.

Research Participants' Perspectives on Precision Diagnostics for Alzheimer's Disease.

BACKGROUND: Understanding research participants' responses to learning Alzheimer's disease (AD) risk information is important to inform clinical implementation of precision diagnostics given rapid advances in disease modifying therapies. OBJECTIVE: We assessed participants' perspectives on the meaning of their amyloid positron emission tomography (PET) imaging results for their health, self-efficacy to understand their results, psychological impact of learning their results, experience receiving their results from the clinical team, and interest in genetic testing for AD risk. METHODS: We surveyed individuals who were being clinically evaluated for AD and received PET imaging six weeks after the return of results. We analyzed responses to close-ended survey items by PET result using Fisher's exact test and qualitatively coded open-ended responses. RESULTS: A total of 88 participants completed surveys, most of whom had mild cognitive impairment due to AD (38.6%), AD (28.4%), or were cognitively unimpaired (21.6%). Participants subjectively understood their results (25.3% strongly agreed, 41.8% agreed), which could help them plan (16.5% strongly agreed, 49.4% agreed). Participants with a negative PET result (n = 25) reported feelings of relief (Fisher's exact p < 0.001) and happiness (p < 0.001) more frequently than those with a positive result. Most participants felt that they were treated respectfully and were comfortable voicing concerns during the disclosure process. Genetic testing was anticipated to be useful for medical care decisions (48.2%) and to inform family members about AD risk (42.9%). CONCLUSIONS: Participants had high subjective understanding and self-efficacy around their PET results and did not experience negative psychological effects. Interest in genetic testing was high.