Molecular imaging in degenerative dementias
Manchester, United Kingdom
35 slide(s) – 00:22:31– English –2010-09-28
Molecular imaging techniques have a broad range of potential targets in dementia research, including cholinergic, serotonergic, and dopaminergic transmitters, transporters, and receptors. Current interest is focussing mainly on amyloid imaging as it relates to the amyloid cascade hypothesis for the pathogenesis of AD, and therefore has a high potential for early and specific diagnosis and for monitoring of targeted therapeutic intervention. The most widely used tracer is the thioflavine derivative 11C-PIB, while related 18F-labeled compounds are better suited as imaging biomarkers for multicenter clinical trials because due to their longer physical half-life (90 min), they do not require a cyclotron onsite. 11C-PIB offers:
(A) high sensitivity for preclinical detection of AD,
(B) provides a robust signal for detection of fibrillary betaamyloid (perivascular and plaques),
(C) is related to ApoE4 status, and
(D) differentiates AD from FTD and from the majority of cases with Parkinson’s disease and dementia, while most patients with Lewy-body dementia also show increased uptake (in accordance with post-mortem findings).
Unresolved issues relate to the clinical significance of increased PIB uptake of aged controls (up to 40% at age 80+), absence of further increase of PIB binding with disease progression after onset ofAD, lack of close relation with severity of symptoms, and weak binding only to oligomeric amyloid which may be the neurotoxic amyloid species. Commercial 18F-labeled amyloid tracers flutemetamol (GE-067), florbetaben (BAY-94-9172) and florpiramine (AV-45) are undergoing clinical trials. Preliminary results indicate properties similar to 11C-PIB with higher nonspecific binding, which may be overcome by most recently developed tracers 11C-AZD2184 and 18FAZD4694. Amyloid scanning is expected to have significant clinical impact by providing diagnostic specificity much earlier than this can be achieved by clinical means for intervention trials that aim at preventing or delaying the onset of dementia. The molecular imaging technique that most closely reflects the progression of synaptic dysfunction and cognitive impairment still is the assessment of cerebral glucose metabolism by FDG PET. Cholinergic dysfunction was demonstrated inAD already before onset of dementia at the clinical stage of mild cognitive impairment using the acetylcholine analogue tracer 11C-MP4A. Serotonergic dysfunction is being analysed by using 11C-DASB, and microglial activation that accompanies neurodegenerative processes has been visualised by using 11C-PK11195 in humans. Thus, PET provides a broad range of specific tools to assess molecular changes in human brain in degenerative dementias.