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Brain Advance Access originally published online on December 7, 2007
Brain 2008 131(1):72-89; doi:10.1093/brain/awm280
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The tauopathy associated with mutation +3 in intron 10 of Tau: characterization of the MSTD family

Salvatore Spina1, Martin R. Farlow2, Frederick W. Unverzagt3, David A. Kareken2, Jill R. Murrell1, Graham Fraser4, Francine Epperson1, R. Anthony Crowther4, Maria G. Spillantini5, Michel Goedert4 and Bernardino Ghetti1

1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA, 2Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA, 3Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA, 4Medical Research Council Laboratory of Molecular Biology, Cambridge, UK and 5Brain Repair Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

Correspondence to: Bernardino Ghetti, M.D., Indiana University School of Medicine, Department of Pathology and Laboratory Medicine, Medical Science Building Room A138, 635 Barnhill Drive, Indianapolis, IN 46202, USA E-mail: bghetti{at}iupui.edu

Multiple system tauopathy with presenile dementia (MSTD) is an inherited disease caused by a (g) to (a) transition at position +3 in intron 10 of Tau. It belongs to the spectrum of frontotemporal dementia and parkinsonism linked to chromosome 17 with mutations in Tau (FTDP-17T). Here we present the longitudinal clinical, neuropsychological, neuroimaging, neuropathological, biochemical and genetic characterization of the MSTD family. Presenting signs were consistent with the behavioural variant of frontotemporal dementia in 17 of 21 patients. Two individuals presented with an atypical form of progressive supranuclear palsy and two others with either severe postural imbalance or an isolated short-term memory deficit. Memory impairment was present at the onset in 15 patients, with word finding difficulties and stereotyped speech also being common. Parkinsonism was first noted 3 years after the onset of symptoms. Neuroimaging showed the most extensive grey matter loss in the hippocampus, parahippocampal gyrus and frontal operculum/insular cortex of the right hemisphere and, to a lesser extent, in the anterior cingulate gyrus, head of the caudate nucleus and the posterolateral orbitofrontal cortex and insular cortex bilaterally. Neuropathologically, progressive nerve cell loss, gliosis and coexistent neuronal and/or glial deposits consisting mostly of 4-repeat tau were present in frontal, cingulate, temporal and insular cortices, white matter, hippocampus, parahippocampus, basal ganglia, selected brainstem nuclei and spinal cord. Tau haplotyping indicated that specific haplotypes of the wild-type allele may act as modifiers of disease presentation. Quantitative neuroimaging has been used to analyse the progression of atrophy in affected individuals and for predicting disease onset in an asymptomatic mutation carrier. This multidisciplinary study provides a comprehensive description of the natural history of disease in one of the largest known families with FTDP-17T.

Key Words: frontotemporal dementia; progressive supranuclear palsy; hippocampus; voxel-based morphometry; Tau haplotype

Abbreviations: FTD, frontotemporal dementia; MSTD, multiple system tauopathy with presenile dementia; NFT, neurofibrillary tangle; CA, cornu ammonis

Received July 18, 2007. Revised September 11, 2007. Accepted October 22, 2007.


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