Frontal Lobe Dementia With Novel Tauopathy: Sporadic Multiple System Tauopathy With Dementia

Journal of Neuropathology and Experimental Neurology Copyright q 2001 by the American Association of Neuropathologists Vol. 60, No. 4 April, 2001 pp. 328 341 Frontal Lobe Dementia With Novel Tauopathy: Sporadic Multiple System Tauopathy With Dementia EILEEN H. BIGIO, MD, ANNE M. LIPTON, MD, PHD, SHU-HUI YEN, PHD, MIKE L. HUTTON, PHD, MATT BAKER, BSC, PARIMALA NACHARAJU, PHD, CHARLES L. WHITE III, MD, PETER DAVIES, PHD, WENLANG LIN, PHD, AND DENNIS W. DICKSON, MD Key Words: Corticobasal ganglionic degeneration; Dementia; Frontal lobe dementia; Frontotemporal degeneration; FTDP17; Progressive supranuclear palsy; Tauopathy. INTRODUCTION Abnormalities in the microtubule-associated protein tau are associated with an array of neurodegenerative disorders, including Alzheimer disease (AD) (1–5), Pick disease (2, 3, 6–9), progressive supranuclear palsy (PSP) (6– 17), corticobasal ganglionic degeneration (CBGD) (6–8, 12, 14, 15, 18), neurofibrillary tangle-predominant senile dementia (NFT-SD) (19), and the frontotemporal degenerations (FTD) (1–4, 20, 21) including frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) (21–51). Tau-positive inclusions are found in neurons, astrocytes, and oligodendrocytes in these disorders (1, 4, 5, 8, 9). In fact, tau-positive tufted astrocytes and glial plaques practically define the pathology of PSP and CBGD (2, 3, 10–17), while in the FTDP-17 families, tau-positive inclusions are more prominent in oligodendrocytes than in astrocytes (1, 4, 5, 9). The frontotemporal degenerations, including the FTDP-17 tauopathies, have similar clinical profiles, with variable impairment of behavioral, cognitive, and motor function (2, 3, 24, 25, 30). They generally present with From the Departments of Pathology, Neuropathology Laboratory (EHB, CLW) and Neurology (AML), University of Texas Southwestern Medical School, Dallas, Texas; Departments of Pharmacology (S-HY, PN) and Neurogenetics (MLH, MB, WL, DWD), Mayo Clinic Jacksonville, Jacksonville, Florida; Department of Pathology (PD), Albert Einstein College of Medicine, Bronx, New York. Correspondence to: Eileen H. Bigio, MD, UT Southwestern Medical School, Dept. of Pathology, Neuropathology Laboratory, 5323 Harry Hines Blvd., Dallas, TX 75390-9073. Supported in part by NIH grant AG12300 for the Alzheimer Disease Center at the University of Texas Southwestern Medical School. abnormalities in behavior and personality, develop dementia and language difficulty, and may develop parkinsonism and eye movement abnormalities (2, 3, 28, 29, 33, 34, 36, 46, 48, 49). Onset is usually younger than in AD, most often in the fifth decade, with familial cases having a younger age of onset than sporadic cases (23, 24, 28, 29, 33, 34, 36, 46, 48, 49). We present a tauopathy with novel inclusions in a patient with a non-familial frontal lobe dementia without parkinsonism. MATERIALS AND METHODS Case History A Caucasian woman began experiencing progressive memory decline at age 75, in 1987. Her speech became simplified and she had difficulty naming objects. She had significant personality and behavior changes with emotional outbursts, increasingly aggressive behavior, and decreased attention to personal hygiene. On the other hand, she had no visuospatial difficulties and was still driving when first evaluated in February of 1990 at age 78. Initial psychiatric evaluation revealed dysnomia, hypofluency, and diminished concentration. On neuropsychologic testing, she had a verbal IQ of 82, performance IQ of 103, and fullscale IQ of 91, with bilateral cerebral hemispheric deficits, left worse than the right. The Mini-Mental State Examination (52) score declined from 26/30 in February of 1990 to 24/30 in July 1991. Her score on the Blessed Dementia Rating Scale (53) deteriorated from 3 on initial evaluation to 4.5 in July of 1991. At her initial evaluation, she had a Clinical Dementia Rating (54) score of 0.5, a Global Deterioration Scale (55) rating of 3, and a modified Hachinski Ischemic Score (56) of 1. Her neurologic examination revealed no focal deficits. MRI of the brain 328 Abstract. We present a novel tauopathy in a patient with a 10-yr history of progressive frontal lobe dementia and a negative family history. Autopsy revealed mild atrophy of frontal and parietal lobes and severe atrophy of the temporal lobes. There were occasional filamentous tau-positive inclusions, but more interesting were numerous distinctive globular neuronal and glial tau-positive inclusions in both gray and white matter of the neocortex. Affected subcortical regions included substantia nigra, globus pallidus, subthalamic nucleus, and cerebellar dentate nucleus, in a distribution similar to progressive supranuclear palsy (PSP), but without significant accompanying neuronal loss or gliosis. Predominantly straight filaments were detected by electron microscopy (EM), while other inclusions were similar to fingerprint bodies. No twisted ribbons were detected. Immuno-EM studies revealed that only the filamentous inclusions were composed of tau. Immunoblotting of sarkosyl-insoluble tau revealed 2 major bands of 64 and 68 kDa. Blotting analysis after dephosphorylation revealed predominantly 4-repeat tau. Sequence analysis of tau revealed that there were no mutations in either exons 9–13 or the adjacent intronic sequences. The unique cortical tau pathology in this case of sporadic multiple system tauopathy with dementia adds a new pathologic profile to the spectrum of tauopathies. 329 SPORADIC MSTD TABLE 1 PHF-1 and Ab Immunohistochemistry Region PHF-1 21 GM, 21 WM 21 GM, 21 WM, rare TA 31 GM, 31WM* 11 GM, 11 WM, rare TA 11 GM, 11 WM 11 GM, 11 WM, rare TA rare 1 nbm neurons, 11 gpi, rare 1 putamen 11 subth., hypoth., periaq. gr.; 31 IC 21 substantia nigra, c.n. III, retic. formation occasional dentate neurons 1 21 GM, 21 WM, rare TA 31 GM, 31 WM, rare TA rare GM, rare TA negative negative negative 21 DP nd nd negative nd nd nd 21 DP 11 NP, 11 AA 21 DP, 21 AA 11 5 mild, 21 5 moderate, 31 5 severe. Abbreviations: GM 5 gray matter neuronal and glial inclusions (includes dense globular inclusions as well as filamentous NFTlike inclusions); WM 5 predominantly oligodendroglial inclusions–dense globular and filamentous; TA 5 tufted astrocyte-like inclusions; * 5 more inclusions where atrophy less severe; nbm 5 nucleus basalis of Meynert, gpi 5 globus pallidus interna; subth. 5 subthalamic nucleus; hypoth 5 hypothalamus; periaq. gr. 5 periaqueductal gray; IC 5 internal capsule; c.n. III 5 cranial nerve III; retic. 5 reticular; nd 5 not done; DP 5 diffuse plaques; NP 5 neuritic plaques; AA 5 amyloid angiopathy. in February of 1990 showed microvascular changes and generalized cerebral atrophy, more prominent in the temporal lobes. All laboratory values, including cerebrospinal fluid examination, were essentially normal. An EEG performed in February 1990 was normal. Although the clinical diagnosis was AD, the presentation was consid (...truncated)