Globular Glial Tauopathy Presenting as Semantic Variant PPA

Introduction

Semantic variant primary progressive aphasia (svPPA) most often is due to TAR DNA-binding protein 43 (TDP-43) pathology¹. Herein, we report a novel case of svPPA due to a globular glial tauopathy.

Case Presentation

The clinical, neuropsychometric and imaging features of this case previously were reported in 2008². Briefly, a 62-year-old woman 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 (Figure 1) occurred at age 71. At age 72, her husband presented evidence of impaired object knowledge; for example, she frequently would use the incorrect silverware (e.g. fork with soup) and was noted to have used toothpaste instead of hand lotion.

Figure 1. Neuropsychologic testing.

All raw scores were converted to scaled scores based on Mayo Older American Normative Studies (MOANS) norms (mean, 10; SD, 3). DRS-Dementia rating scale; AVLT-delay indicates retention on the Auditory Verbal Learning Test; BNT, Boston Naming Test; COWAT, Controlled Oral Word Association Test; JLO, Judgment of Line Orientation; Rey-O, Rey-Osterrieth Complex Figure Test; TMT, Trail Making Test; WAIS-BD, Block Design subtest of the Wechsler Adult Intelligence Scale–Revised; WMS-LM, Logical Memory of the Wechsler Memory Scale–Revised; Stroop CW, Stroop color-word test.

At age 73, disinhibition became more prominent. Her husband described an incident in which she was cooking steaks for dinner. He told her that he did not want to eat steak and that she should eat without him. She then took a rare steak immediately out of the pan and ate it. Her judgement continued to deteriorate as she would inappropriately pick up hot objects with her hands. At age 75, she returned for follow-up and it was noted that despite her continued deterioration in most cognitive aspects, she expanded her painting artistry. At age 76, 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 suffering the stroke, she died at age 76. Neuropathologic evaluation revealed the pathologic substrate to be a globular glial tauopathy (GGT) and not TDP-43. Gross findings include severe frontotemporal atrophy (temporal > frontal) with left hemibrain weight of 515 grams. Histopathologic features are illustrated in Figure 2.

Figure 2. Histopathology demonstrating globular glial tauopathy.

Histopathology: Globular glial tauopathy, type I, with 4R tau positive globular glial inclusions, predominantly oligodendroglial and to a lesser extent astrocytic. The Gallyas stain was positive in oligodendroglial and negative in astrocytic lesions, as is typical of GGT. There were no TDP43-positive inclusions.

a. Temporal white matter (H&E, x200; inset x750)

b. Temporal white matter (Gallyas, x200; inset x750)

c. Temporal white matter (phospho-tau (AT8), x200)

d. Temporal white matter (4R tau,x200)

e. Temporal gray matter (phospho-tau (AT8), x200; inset: 4R tau x400)

f. Temporal gray matter (Gallyas, x200)

Discussion

To our knowledge, this is a unique case of svPPA due to a GGT. This variant of PPA is due to TDP-43 pathology in approximately 80% of cases¹. Frontotemporal lobar degeneration due to tau (FTLD-tau) is the second most common cause of svPPA, but the cases reported to date typically have been due to Pick disease¹, which is a 3R tauopathy. Mutations in the microtubule associated protein tau (MAPT) have been associated with a “semantic like” presentation, but many of these cases have a predominantly behavioral presentation with secondary semantic dysfunction³. In the present case, the patient clearly met consensus criteria for svPPA for many years before behavioral symptoms evolved. Interestingly, she also developed increased artistic skill similar to other temporal predominant FTDs⁴.

GGTs (4R tauopathy) are subtypes of FTLD-tau characterized by globular tau-reactive oligodendroglial and astrocytic inclusions. GGTs are subdivided into three types based on the distribution of the inclusions⁵. 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 disease⁵. The only prior cases of PPA with GGT pathology have been agrammatic-nonfluent PPA⁵.

Conclusions

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