Exonic and intronic mutations in Tau cause familial neurodegenerative syndromes characterized by frontotemporal dementia and dysfunction of multiple cortical and subcortical circuits. Here we describe a G389R mutation in exon 13 of Tau. When 38 years old, the proband presented with progressive aphasia and memory disturbance, followed by apathy, indifference, and hyperphagia. Repeated magnetic resonance imaging showed the dramatic progression of cerebral atrophy. Positron emission tomography revealed marked glucose hypometabolism that was most severe in left frontal, temporal, and parietal cortical regions. Rigidity, pyramidal signs and profound dementia progressed until death at 43 years of age. A paternal uncle, who had died at 43 years of age, had presented with similar symptoms. The proband's brain showed numerous tau-immunoreactive Pick body-like inclusions in the neocortex and the fascia dentata of the hippocampus. In addition, large numbers of tau-positive filamentous inclusions were present in axons in the frontal, temporal, and parietal lobes. Immunoblot analysis of sarkosyl-insoluble tau showed 2 major bands of 60 and 64 kDa. Upon dephosphorylation, these bands resolved into 4 bands consisting of three- and four-repeat tau isoforms. Most isolated tau filaments were straight and resembled filaments found in Alzheimer disease and some frontotemporal dementias with tau mutations. A smaller number of twisted filaments was also observed. Biochemically, recombinant tau proteins with the G389R mutation showed a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. Taken together, the present findings indicate that the G389R mutation in Tau can cause a dementing condition that closely resembles Pick's disease.

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Purpose Diffusion tensor imaging is a magnetic resonance technique that provides information about the orientation and anisotropy of the white matter tracts. The aim of this study was to analyse diffusion tensor imaging quantitative parameters in idiopathic normal pressure hydrocephalus patients, in order to determine whether this method could correlate to clinical scores and cerebrospinal fluid flowmetry data. Methods and materials Fifteen consecutive patients with idiopathic normal pressure hydrocephalus and 15 age-matched controls underwent cerebrospinal fluid flowmetry and diffusion tensor imaging using a 1.5 Tesla system. Fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity values were calculated using region of interest atlas-based tract-mapping in nine cerebral areas and compared among the two groups. In addition, for idiopathic normal pressure hydrocephalus patients, diffusion tensor imaging parameters were correlated to clinical scores (mini mental state examination and frontal assessment battery) and cerebrospinal fluid flowmetry data. Results Mean fractional anisotropy was significantly lower for the idiopathic normal pressure hydrocephalus group than for the control group in the forceps minor and motor cortex; the idiopathic normal pressure hydrocephalus group had significantly higher mean axial diffusivity for the genu of the corpus callosum and forceps minor. We did not find significant correlation between diffusion tensor imaging parameters and cerebrospinal fluid flowmetry and mini mental state examination, while we observed a correlation between forceps minor fractional anisotropy and frontal assessment battery; no correlation between flowmetry and clinical scores was found. Conclusion Our findings suggest that diffusion tensor imaging provides a non-invasive biomarker of white matter changes in idiopathic normal pressure hydrocephalus patients. Forceps minor is the best site to analyse. As diffusion tensor imaging offers a better correlation to clinical status than cerebrospinal fluid flowmetry, it should be included in the routine idiopathic normal pressure hydrocephalus protocol.

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