Clinicopathologic assessment and imaging of tauopathies in neurodegenerative dementias

Abstract

Microtubule-associated protein tau encoded by the MAPT gene binds to microtubules and is important for maintaining neuronal morphology and function. Alternative splicing of MAPT pre-mRNA generates six major tau isoforms in the adult central nervous system resulting in tau proteins with three or four microtubule-binding repeat domains. In a group of neurodegenerative disorders called tauopathies, tau becomes aberrantly hyperphosphorylated and dissociates from microtubules, resulting in a progressive accumulation of intracellular tau aggregates. The spectrum of sporadic frontotemporal lobar degeneration associated with tau pathology includes progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. Alzheimer's disease is considered the most prevalent tauopathy. This review is divided into two broad sections. In the first section we discuss the molecular classification of sporadic tauopathies, with a focus on describing clinicopathologic relationships. In the second section we discuss the neuroimaging methodologies that are available for measuring tau pathology (directly using tau positron emission tomography ligands) and tau-mediated neuronal injury (magnetic resonance imaging and fluorodeoxyglucose positron emission tomography). Both sections have detailed descriptions of the following neurodegenerative dementias - Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease.

Figure 1

Neuropathologic inclusions seen in tauopathies range from intracellular to extracellular and from neuron to glia. Alzheimer’s disease neuropathologic inclusions used to classify severity based on an ABC scoring scheme include (a) extracellular amyloid-beta (Aβ) plaque (33.1.1 antibody), (b) neurofibrillary tangle (NFT) composed of abnormal tau fibrils (paired helical filament phosphorylated tau antibody), and (c) Aβ deposits surrounded by dystrophic neurites produce neuritic plaques (observed with Bielschowsky silver stain). Tau immunohistochemistry in progressive supranuclear palsy shows abnormal tau aggregates in (d) astrocytes called tufts or tufted astrocytes, (e) neurons called globose NFTs, and (f) oligodendrocytes termed coiled bodies. Tau-immunoreactivity in corticobasal degeneration (CBD) shows abnormal tau aggregates in (g) astrocytes called astrocytic plaques and tau-immunoreactive threads in the gray and white matter in neocortical and subcortical regions and (h) swollen, achromatic or ballooned neurons (hematoxylin and eosin). (i) Tau-immunoreactive, dense spherical neuronal cytoplasmic inclusions called Pick bodies are observed in granular neurons of the dentate fascia in Pick’s disease. (a), (b), (c) Medial temporal cortex. (d), (e), (f),(g), (i) Phospho-tau antibody CP13. (d), (f) Red nucleus at the level of the oculomotor nerve. (e) Substantia nigra. (g), (h) Mid-frontal cortex.

Figure 2

Ultrastructural characterization of tau filaments in Alzheimer’s disease and frontotemporal lobar degeneration tau. (Top, left) Alzheimer’s disease (AD) tau fibrils form paired helical filaments typically observed in flame-shaped cytoplasmic inclusion. (Top, middle) Progressive supranuclear palsy (PSP) tau fibrils typically form straight filaments with rare twisted filaments, similar to corticobasal degeneration (CBD), that aggregate in less compact bundles associated with dense granular material. (Top, right) Pick’s disease (PiD) tau fibrils are mainly straight filaments with some loosely twisted wide filaments that aggregate in close proximity and can be associated with dense granular material. (Bottom, left) Electron micrograph of tau filaments from AD showing paired helical filaments (PHF) and straight filament (SF). Bar, 50 nm. (Bottom, right) Twisted filaments in PSP, CBD and PiD have longer periodicity. Bar, 100 nm. Arrows point at twists of filaments.

Figure 3

Tau ligand binding patterns in progressive supranuclear palsy. (Left) Typical 2-(1-(6-((2-[¹⁸F]fluoroethyl) (methyl)amino)-2-naphthyl)ethylidene) malononitrile ([¹⁸F]-FDDNP) binding patterns seen in advanced progressive supranuclear palsy (PSP), early PSP and Parkinson’s disease. [¹⁸F]-FDDNP signal due to tau binding seen in the basal ganglia, midbrain and pons in PSP subjects but not in Parkinson’s disease. (Right) Sagittal magnetic resonance imaging (MRI) scan of a PSP patient with characteristic midbrain atrophy. DVR, distribution volume ratio, a scaled measure that indicates the linear function of radioligand binding. Reprinted with permission from [98].

Figure 4

Amyloid imaging of Alzheimer’s disease and frontotemporal dementia. Typical amyloid positron emission tomography (Pittsburgh Compound B-PET), fluorodeoxyglucose (FDG)-PET and magnetic resonance imaging (MRI) images seen in a cognitively normal individual (CN), an Alzheimer’s disease (AD) patient and a frontotemporal dementia (FTD) patient. The CN individual shows no evidence of amyloid deposition, normal metabolic uptake and normal structural MRI scan. The AD patient shows significant amyloid uptake throughout the brain, significant low parietal lobe FDG uptake and significant ventricular expansion on the MRI scan. The FTD patient shows no significant amyloid deposition, significant frontal and temporal lobe deficits and atrophy, which are both highly asymmetric.