These criteria were revised recently by the international working group for new research criteria for the diagnosis of AD . The cardinal sellckchem features are late-onset impairment of short-term recall [4,5] associated with deterioration of language and visuo-spatial functions [6,7] in the absence of disturbance of consciousness and systemic disorders. A postmortem diagnosis of AD is based on the presence of extracellular senile plaques positive for ??-amyloid protein (A??), dystrophic neurites, and intracellular neurofibrillary tangles in the brain. Neurofibrillary tangles contain a hyperphosphorylated form of the microtubule-associated protein, tau, and also ubiquitin . Amyloid plaques are composed of 40 to 42 amino acid A??-folded peptides.
Two types of amyloid plaques are present in neurodegenerative diseases: one with a central core and radiating fibrils, the fibrillar amyloid; and second, the diffuse (amorphous) amyloid. A small degree of AD-like pathology can be found in cognitively normal individuals over the age of 75 but large deposits of amyloid suggest AD. Until a few years ago, magnetic resonance imaging (MRI) and cerebral blood flow studies were the only methods by which we could gain information about the changes in the living human brain. Structural MRI and blood flow studies, however, depend on gross changes in brain structure and function that suggest gross atrophy or a functional alteration that has already occurred. These markers are thus secondary phenomena and are therefore not the primary targets for following patients over a period of time or for diagnosing very early and subtle changes.
Clinico-pathological studies suggest that neuronal loss has already occurred by the time gross atrophy is detected by MRI. Positron emission tomography (PET) with [18F]fluorodeoxyglucose adds to the diagnostic and prognostic accuracy in the clinical evaluation of AD , but the technique still detects an indirect measure of disease presence or progression. Modification of the polar amyloid binding histological dye, thioflavin T, led to the finding that neutral benzothiazoles bind to amyloid with high affinity and additionally cross the blood-brain barrier . The benzothiazole amyloid binding agent 2-(4′-methyl-aminophenyl)-benzothiazole and related compounds bind to amyloid with low nanomolar affinity, enter the brain in amounts sufficient for imaging with PET and clear rapidly from normal brain tissue [11,12].
At the low nanomolar concentrations typically administered during PET studies, 2-(4′-methyl-amino-phenyl)-benzothiazole binds to extracellular amyloid plaques in postmortem brain slices but not to intracellular AV-951 neurofibrillary tangles. In vitro studies suggest that, while 2-(4′-methyl-amino-phenyl)-benzothiazole binds to fibrillar A?? deposits found in the cortex selleck inhibitor and striatum, it does not bind to amorphous A?? deposits found in the cerebellum.
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