Case study: First PIB PET Alzheimers patient shows molecular changes

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A case study of the first patient with Alzheimer’s disease who underwent PET imaging with the amyloid tracer, Pittsburgh Compound B (PIB) to visualize fibrillar beta-amyloid in the brain both during progression of the disease and after death has been published online Dec. 13 in the journal Brain.

The patient underwent PET studies with 18F-FDG three times (at ages 53, 56 and 58 years) and twice with PIB (at ages 56 and 58 years), prior to death at 61 years of age, according to Agneta Nordberg, MD, PhD, professor and head of the division of Alzheimer neurobiology, Karolinska Institutet in Stockholm. After the patient died, the team carried out pathological and neurochemical analyses of the brain tissue.

The patient showed a pronounced decline in cerebral glucose metabolism and cognition during disease progression, while PIB retention remained high and stable at follow-up. Neuropathological examination of the brain at autopsy confirmed the clinical diagnosis of pure Alzheimer’s disease.

Regional in vivo 11C-PIB-PET retention positively correlated with 3H-PIB binding, total insoluble beta-amyloid and beta-amyloid plaque distribution, but not with the number of neurofibrillary tangles measured at autopsy. In addition, a positive correlation was found between regional 11C-PIB PET retention and 3H-PIB binding with the number of glial fibrillary acidic protein immunoreactive cells, added Nordberg and colleagues.

The combined result analyses have given a detailed picture of how Alzheimer's develops, according to Nordberg and colleagues. For example, the results showed that high concentrations of amyloid plaques were discovered at an early stage of the disease when the patient suffered slight memory loss. The levels remained unchanged during the course of the disease, in contrast to the increasingly declining energy metabolism in the brain, which was also measured using PET as the patient's memory gradually deteriorated, noted the researchers.

One formerly unknown connection that was discovered in the study is that the greater accumulation of plaque is accompanied by a reduction in the number of neuronal nicotinic receptors in the brain. There was a negative correlation between regional fibrillar beta-amyloid and levels of 3H-nicotine binding.

Further, inflammatory changes were measured in brain regions with low levels of plaques which suggest that the neuroinflammation related to Alzheimer's disease might have a different cause and evolve at different stage of the disease compared to that of amyloid accumulation. Studies on this are currently being carried out on living patients using PET imaging.

In summary, high 11C-PIB PET retention significantly correlates with both fibrillar beta-amyloid and losses of neuronal nicotinic acetylcholine receptor subtypes at autopsy, suggesting a closer involvement of beta-amyloid pathology with neuronal nicotinic acetylcholine receptor subtypes than with inflammatory processes.

"If we combine different exams, we will be able to affirm that complex changes take place at the same time in the brain during the development of Alzheimer's disease," says Nordberg. "Our study shows that new, modern imaging technology known as molecular imaging makes it possible to discover the disease at an early stage. This opens up new opportunities for early diagnosis and for understanding the causes of the disease and identifying patients who can be expected to respond well to future Alzheimer's therapy."