Molecular Imaging of Extrapyramidal Movement Disorders With Dementia: The 4R Tauopathies

Abstract

Two pathologically distinct neurodegenerative conditions, progressive supranuclear palsy and corticobasal degeneration, share in common deposits of tau proteins that differ both molecularly and ultrastructurally from the common tau deposits diagnostic of Alzheimer disease. The proteinopathy in these disorders is characterized by fibrillary aggregates of 4R tau proteins. The clinical presentations of progressive supranuclear palsy and of corticobasal degeneration are often confused with more common disorders such as Parkinson disease or subtypes of frontotemporal lobar degeneration. Neither of these 4R tau disorders has effective therapy, and while there are emerging molecular imaging approaches to identify patients earlier in the course of disease, there are as yet no reliably sensitive and specific approaches to diagnoses in life. In this review, aspects of the clinical syndromes, neuropathology, and molecular biomarker imaging studies applicable to progressive supranuclear palsy and to corticobasal degeneration will be presented. Future development of more accurate molecular imaging approaches is proposed.

Figure 1:

Cerebral glucose metabolic examples of subjects with clinical syndromes associated with Parkinsonism and dementia. In each section, the top row of images depicts surface-rendering of cerebrocortical FDG activity. Colored voxels represent regions of significantly reduced metabolism compared to a database of normal subjects according to the key at bottom right of the figure: −1.5 SD (light blue) to −5 SD (dark violet). The second row of images in each section depicts selected transaxial levels from dorsal (image left) to ventral (image right). Regions of reduced metabolic activity are indicated by blue arrowheads; regions of increased activity are depicted by red arrowheads. A: Corticobasal Syndrome. Glucose hypometabolism in the right primary somatosensory cortex and the right thalamus. B: Progressive Supranuclear Palsy – Richardson Syndrome. Glucose hypometabolism in bilateral sensorimotor cortices, striatum, thalamus and in the midbrain. C: Dementia with Lewy Bodies. Glucose hypometabolism in bilateral temporoparietal association cortices and in left greater than right primary visual cortices. Glucose metabolism is increased in the striatum bilaterally as can be seen in nigrostriatal degeneration in the absence of dopamine replacement therapy. D: Primary Progressive Non-Fluent Aphasia. Glucose hypometabolism in the left mid-frontal cerebral cortex (Broca’s area). E: Behavioral Variant Frontotemporal Lobar Degeneration. Glucose hypometabolism in bilateral prefrontal association cortices.

Figure 1:

Cerebral glucose metabolic examples of subjects with clinical syndromes associated with Parkinsonism and dementia. In each section, the top row of images depicts surface-rendering of cerebrocortical FDG activity. Colored voxels represent regions of significantly reduced metabolism compared to a database of normal subjects according to the key at bottom right of the figure: −1.5 SD (light blue) to −5 SD (dark violet). The second row of images in each section depicts selected transaxial levels from dorsal (image left) to ventral (image right). Regions of reduced metabolic activity are indicated by blue arrowheads; regions of increased activity are depicted by red arrowheads. A: Corticobasal Syndrome. Glucose hypometabolism in the right primary somatosensory cortex and the right thalamus. B: Progressive Supranuclear Palsy – Richardson Syndrome. Glucose hypometabolism in bilateral sensorimotor cortices, striatum, thalamus and in the midbrain. C: Dementia with Lewy Bodies. Glucose hypometabolism in bilateral temporoparietal association cortices and in left greater than right primary visual cortices. Glucose metabolism is increased in the striatum bilaterally as can be seen in nigrostriatal degeneration in the absence of dopamine replacement therapy. D: Primary Progressive Non-Fluent Aphasia. Glucose hypometabolism in the left mid-frontal cerebral cortex (Broca’s area). E: Behavioral Variant Frontotemporal Lobar Degeneration. Glucose hypometabolism in bilateral prefrontal association cortices.

Figure 2:

Structures of radioligands reported in PET investigations of 4R tauopathies. T807 is additionally known as AV-1451 or as Flortaucipir-F18.