Neurodegenerative Disease Alzheimer’s Disease
Figure 2: Acetylcholine Esterase Activity in Alzheimer’s Disease Compared with Dementia
the relatively high level of non-specific binding resulting in unfavorable signal strength. A recent study using the R-isomer according to current standards,53
on the other hand, found moderately increased binding.
Thus, there is a need for the development of better tracers, ideally labeled with fluorine-18, for clinical use. A large number of new tracers have been tested in experimental animals.54
Initial clinical studies using
various tracers have detected that there is an as yet unidentified genetic polymorphism that leads very low binding with some of the new tracers in about one-fourth of normal individuals tested so far.55,56
Mild Alzheimer dementia MMSE 23
Severe Alzheimer dementia MMSE 10
Dementia with Lewey Bodies MMSE 19
Positron emission tomography scans of acetylcholine esterase activity (accumulation of 11C-MP4A 30 to 60 minutes after injection) in two patients with Alzheimer’s disease showing reduction of cortical activity compared with more extensive reduction in dementia with Lewy bodies (arrows mark the brain areas with the most severe reduction). MMSE = Mini Mental State Examination.
tracer binding with the amount of post-mortem Aβ deposition, as shown for florbetapir at the International Conference on Alzheimer’s Disease (ICAD) 10 conference.40
Another F-18-labeled amyloid tracer is 2-(1-(6-[(2-[F-18]fluoroethyl) (methyl)amino]-2-naphthyl)ethylidene)malononitrile, abbreviated to FDDNP, which binds to Aβ with less affinity than PIB and related compounds.41
It competes with non-steroidal antiphlogistics42 when
binding and has significant affinity to pathological intracellular tau deposits (neurofibrillary tangles). These deposits are mainly located in the hippocampus in AD and also occur in other neurodegenerative diseases. Accordingly, a gradual increase in binding was observed in MCI and AD patients, mainly in the hippocampus but also in brain areas with predominant Aβ deposits.43
Direct comparison with C-11-PIB
demonstrated the differences in spatial distribution, and greater overlap between controls and patients than with C-11-PIB.44,45
Microglial Activation
Microglia are the resident immune cells of the brain. In response to brain damage, microglia undergo changes in their morphology, migrate toward the lesion site, proliferate, and produce cytokines and reactive oxygen species. This is associated with expression of the peripheral benzodiazepine receptor, which is known to be located at the mitochondrial translocator protein.46
sites of aggregated Aβ deposition in the brains of AD subjects47
Activated microglia are present at and may
contribute to Aβ removal. However, the secretion of cytokines associated with microglial activation may also contribute to tissue damage and apoptosis. Further research with longitudinal assessment of microglial activation in humans is therefore needed to understand its consequences and whether it is a major factor that influences the rate of disease progression.48
The in vivo PET findings in AD are not particularly clear. An early study using racemic 11C-PK11195 was negative,52
30
Tracers for Microglial Activation Imaging The first tracer that became available for imaging of microglial activation in humans was 11C-PK11195. This has been shown to largely reflect the distribution of activated microglia in experimental and human brain disease,49,50 atropy.51
demonstrating microglial activation in multiple system probably due to
complicates the clinical application of such tracers. Glucose Metabolism
Cerebral glucose metabolism is measured by the most widely available PET tracer, 18F-2-fluoro-D-deoxyglucose (FDG). There is close coupling of glucose metabolism with neuronal function.57
Glucose is the main
substrate for the energy production that is required to maintain neuronal ion gradients for neuronal activity. Coupling to synaptic activity is also mediated by the neuron-astrocyte glutamate shuttle.58,59
Over more than 20 years, multiple studies have demonstrated that glucose metabolism and blood flow are imparied in temporal-parietal association cortices, with the angular gyrus usually being located at the center of the metabolic impairment.60
This
The frontal association cortex may
also be involved, but more variably so and usually to a lesser degree and only during progression of AD. There may be a distinct hemispheric asymmetry, which usually corresponds to the predominant cognitive deficits (language impairment in the dominant and visuospatial disorientation in the sub-dominant hemisphere).
In contrast to other dementia types, glucose metabolism in basal ganglia, primary motor, visual cortex, and cerebellum is usually well preserved. This pattern generally reflects the clinical symptoms of AD, with impairment of memory and associative thinking, including higher-order sensory processing and planning of action, but with relative preservation of primary motor and sensory function. Glucose metabolism provides high diagnostic power, especially when used in combination with automated objective image evaluation software.61,62
As such, it has been recommended in current guidelines for dementia diagnosis.63
Longitudinal studies have demonstrated that the severity and extent of metabolic impairment in the temporal and parietal cortex increases with dementia progression and frontal reductions become more evident.64,65 The annual decrease of metabolism in association cortices is 5–6%.66,67 Asymmetrical metabolic impairment and associated predominance of language or visuospatial impairment tends to persist during progression.68,69
Based on these observations, FDG PET can serve as a surrogate marker in therapeutic trials.70–72
There are several indications that increased activation in some parts of the brain may provide compensation for the failure of function in other parts.73
During the pre-dementia stages of AD, frontal brain function may compensate for the failure of the Papez circuit—which includes the hippocampus and is essential for acquisition of long-term memory—as well as posterior association cortices. The prefrontal cortex was the
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