Globular Glial Tauopathy Presenting as Semantic Variant Primary Progressive Aphasia

Semantic variant primary progressive aphasia (svPPA) most often is due to TAR DNA-binding protein 43 (TDP-43) pathology.¹ Herein, we report a case of svPPA due to a globular glial tauopathy (GGT).

The clinical, neuropsychometric, and imaging features of this case previously were reported in 2008.² Briefly, a woman in her 60s was referred to the Behavioral Neurology Clinic for memory loss, characterized by difficulty remembering names. Longitudinal evaluations revealed progressive anomia with loss of word knowledge, prosopagnosia, and surface dyslexia. Her last completed neuropsychometric evaluation occurred at age 71 years (Figure 1). In her early 70s, her husband presented evidence of impaired object knowledge; for example, she frequently would use the incorrect silverware (eg, fork with soup) and was noted to have used toothpaste instead of hand lotion.

At age 73 years, disinhibition became more prominent. Her judgment continued to deteriorate as she would inappropriately pick up hot objects with her hands. In her mid-70s, she returned for follow-up and it was noted that despite her continued deterioration in most cognitive aspects, she had expanded her painting artistry. Later in her mid-70s, she was placed in a nursing home following a right hemispheric infarct. In the last few months of life, she developed significant echolalia. Three months after having a stroke, she died in her mid-70s. Neuropathologic evaluation revealed the pathologic substrate to be a GGT and not TDP-43. Gross findings included severe frontotemporal atrophy (temporal > frontal), with left hemibrain weight of 515 g. Histopathologic features are illustrated in Figure 2.

This is a rare case of svPPA due to a GGT. This variant of PPA is due to TDP-43 pathology in approximately 80% of cases.¹ Frontotemporal lobar degeneration due to tau is the second most common cause of svPPA; however, the cases reported to date typically have been due to Pick disease,¹ which is a 3R tauopathy. Mutations in the microtubule-associated protein tau gene have been associated with a semantic-like presentation, but many of these cases have a predominantly behavioral presentation with secondary semantic dysfunction.³ In the present case, the patient clearly met consensus criteria for svPPA for many years before behavioral symptoms evolved. She also developed increased artistic skill similar to other temporal predominant frontotemporal dementias.⁴

Globular glial tauopathies (4R tauopathy) are subtypes of frontotemporal lobar degeneration due to tau characterized by globular tau-reactive oligodendroglial and astrocytic inclusions. Globular glial tauopathies are subdivided into 3 types based on the distribution of the inclusions.⁵ In this case, frontotemporal globular oligodendroglial inclusions dominated (type I).

The clinical presentations of GGTs are variable and include behavioral variant frontotemporal dementia, progressive supranuclear palsy, primary lateral sclerosis, corticobasal syndrome, and combinations of dementia, parkinsonism, and motor neuron disease.⁵ Prior cases of PPA with GGT pathology have been agrammatic-nonfluent PPA.⁵

These findings expand the pathologic substrate of svPPA to include GGTs.

Corresponding Author: Bradley F. Boeve, MD, Mayo Clinic, 200 1st St SW, Rochester, MN 55905 (bboeve@mayo.edu).

Published Online: November 16, 2015. doi:10.1001/jamaneurol.2015.2711.

Author Contributions: Dr Graff-Radford had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors reviewed the manuscript and were in agreement with its content and provided final approval of the version to be published.

Study concept and design: Graff-Radford, Josephs, Parisi, Boeve.

Acquisition, analysis, or interpretation of data: Graff-Radford, Parisi, Dickson, Giannini, Boeve.

Drafting of the manuscript: Graff-Radford.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Parisi, Giannini, Boeve.

Study supervision: Josephs, Parisi, Giannini, Boeve.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by grant P50 AG16574 from the National Institutes of Health.

Role of the Funder/Sponsor: The National Institutes of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.