Francine Epperson

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

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.

PET of Brain Prion Protein Amyloid in Gerstmann–Sträussler–Scheinker Disease

In vivo amyloid PET imaging was carried out on six symptomatic and asymptomatic carriers of PRNP mutations associated with the Gerstmann–Sträussler–Scheinker (GSS) disease, a rare familial neurodegenerative brain disorder demonstrating prion amyloid neuropathology, using 2‐(1‐{6‐[(2‐[F‐18]fluoroethyl)(methyl)amino]‐2‐naphthyl}ethylidene)malononitrile ([F‐18]FDDNP). 2‐Deoxy‐2‐[F‐18]fluoro‐d‐glucose PET ([F‐18]FDG) and magnetic resonance imaging (MRI) scans were also performed in each subject.

Phenotypic variability in three families with valosin-containing protein mutation

The phenotype of IBMPFD [inclusion body myopathy with Pagets disease of the bone and frontotemporal dementia (FTD)] associated with valosin‐containing protein (VCP) mutation is described in three families.

Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene: a neuropathologic and neuroanatomical study of four siblings

Rapid-onset dystonia-parkinsonism (RDP) is a movement disorder associated with mutations in the ATP1A3 gene. Signs and symptoms of RDP commonly occur in adolescence or early adulthood and can be triggered by physical or psychological stress. Mutations in ATP1A3 are also associated with alternating hemiplegia of childhood (AHC). The neuropathologic substrate of these conditions is unknown. The central nervous system of four siblings, three affected by RDP and one asymptomatic, all carrying the I758S mutation in the ATP1A3 gene, was analyzed. This neuropathologic study is the first carried out in ATP1A3 mutation carriers, whether affected by RDP or AHC. Symptoms began in the third decade of life for two subjects and in the fifth for another. The present investigation aimed at identifying, in mutation carriers, anatomical areas potentially affected and contributing to RDP pathogenesis. Comorbid conditions, including cerebrovascular disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relevant to RDP separately from those affected by the comorbid conditions. Anatomical areas identified as potential targets of I758S mutation were globus pallidus, subthalamic nucleus, red nucleus, inferior olivary nucleus, cerebellar Purkinje and granule cell layers, and dentate nucleus. Involvement of subcortical white matter tracts was also evident. Furthermore, in the spinal cord, a loss of dorsal column fibers was noted. This study has identified RDP-associated pathology in neuronal populations, which are part of complex motor and sensory loops. Their involvement would cause an interruption of cerebral and cerebellar connections which are essential for maintenance of motor control.

COMPARATIVE ANALYSIS OF PIB IN VIVO WITH 6-CN-PIB AND Aβ-IMMUNOHISTOCHEMISTRY POSTMORTEM IN FAMILIAL ALZHEIMER DISEASE ASSOCIATED WITH THE PSEN1 I229F MUTATION

low numbers of participants, relatively long intervals between imaging and death, and low level of detail in terms of the spatial patterns of brain atrophy. The purpose of this investigation was to assess the neuropathologic correlates of regional brainvolumes by combining ex-vivoMRvolumetry and pathology on a large community cohort of older persons. Methods: Cerebral hemispheres were obtained from 166 deceased participants of two longitudinal, epidemiologic clinical-pathologic cohort studies of aging. All hemispheres were imaged ex-vivo, while immersed in 4% formaldehyde solution, on a 3T MRI scanner. A multi-atlas approach was used to segment ex-vivo MRI data intowhite and gray matter, and graymatter into 34 cortical and 8 subcortical regions. The volumes of all regions were normalized by the height of the participants. Following imaging, hemispheres underwent neuropathologic examination. The pathologies that were considered in analyses were: Alzheimer’s disease (AD) pathology, Lewy bodies, hippocampal sclerosis, gross and microscopic chronic infarcts, and cerebral amyloid angiopathy. Multiple linear regression was used to investigate the link between regional volumes and neuropathologies, controlling for age at death, sex, education, postmortem interval to fixation and to imaging. False Discovery Rate (FDR) was used to correct for multiple comparisons.Results: Figure 1 shows brain regions with significant negative correlation (p<0.05, FDR-corrected) between their volume and AD pathology (Fig.1A), and hippocampal sclerosis (Fig.1B). No other pathologies showed significant correlations with the volume of the segmented regions. Conclusions: The present study provides information on the neuropathologic correlates of regional brain volumes in a community cohort of older adults, and may help in the development of imaging biomarkers of AD pathology and hippocampal sclerosis. To our knowledge, this is the largest MR volumetry pathology investigation to date, and the only assessing a high number of brain regions.

ALTERED FMRI ACTIVATION PATTERN DURING VISUAL SCENE ENCODING IN AFFECTED AND NON-AFFECTED CARRIERS OF PSEN1 AND APP MUTATIONS

Background: Several studies highlighted the differential effect of normal and pathological aging on hippocampal subfield volumes, suggesting that these measurements may be more accurate than global hippocampal volumetry to detect early Alzheimer’s disease (AD). For clinical application, validated automatic algorithms of hippocampal subfield segmentation are urgently needed. An increasing number of studies use the automatic segmentation algorithm implemented in FreeSurfer. However, this approach has not been validated so far on AD patients. This study aimed to compare the accuracy of T1-MRI-based FreeSurfer segmentation versus manual delineation on dedicated high-resolution scan in measuring hippocampal subfield volumes and the effects of age and AD on these volumes. Methods: Hippocampal subfields were segmented in 98 healthy individuals (aged 19 to 84), 17 MCI and 18 AD patients using both FreeSurfer (T1-MRI, resolution: 1*1*1mm) and manual delineation (proton density-MRI, resolution: 0.375*0.375*2mm). Intraclass correlation coefficients (ICC) and Bland-Altman plots were computed to assess the consistency between both methods, and the effects of age (regressions) and group (ANOVAs) were assessed for both Freesurfuer and manual measurements. Results: Moderate to high ICCs were found for the subiculum and other subfields as well as for the whole hippocampus, but the ICC was very low for CA1. Using manual delineation, age was found to have a linear effect on the subiculum and a nonlinear (later) effect on CA1 volumes. A graded effect of the pathology was found on CA1, subiculum and the other subfields volumes. FreeSurfer CA1 volumes were found to be lower than those obtained from manual segmentation. This bias was proportional to the volume of this structure so that no effect of age or AD could be detected on FreeSurfer CA1 volumes. Conclusions: This study highlights differences in the anatomic definition of the subfields, especially for CA1, between FreeSurfer and manual delineation based on histologic atlases. While FreeSurfer provides reasonable estimates of the subiculum and other subfields, it does not provide a reliable estimate of CA1 volume and fails in detecting normal aging and AD-related changes in this subfield. As earliest AD-related changes seem to occur in CA1, FreeSurfer needs to be improved especially for clinical application in early AD diagnosis.

PSEN1 M233V MUTATION CAUSES VERY EARLY ONSET ALZHEIMER DISEASE: THE IMPORTANCE OF NEUROPATHOLOGIC ARCHIVAL TISSUE

Background: Functional connectivity in the default mode network (DMN) has been proposed as an early biomarker in amnestic lateonset Alzheimer’s disease (AD). Connectivity in the DMN and other networks has been less explored in early-onset AD patients, who present with greater clinical and anatomic heterogeneity, including focal non-amnestic presentations. Methods: The study included resting-state functional MRI scans of 64 non-familial AD patients (Table), including 23 with early-onset AD (EO-AD, age at onset <65 years, predominant amnestic/dysexecutive deficits), 25 with logopenic variant primary progressive aphasia (lvPPA, predominant language deficits) and 16 patients with posterior cortical atrophy (PCA, predominant visual deficits). 70 healthy controls were also included for comparison. Seed-based connectivity analyses were conducted using the peak intensity voxels of network templates (http://findlab.stanford.edu/functional_ROIs.html) for 3 DMN components (anterior, posterior and ventral), as well as 4 non-DMN networks clinically involved in AD variants: left and right executive-control, language and higher visual networks. Z scores were extracted from the resulting connectivity maps in each subject. Group comparisons were performed for all AD patients compared with controls as well as for individual AD variant groups, adjusting for age and gender. Results: Comparing all AD patients with controls, we found significantly reduced connectivity in the executive-control, language and higher visual networks (p<0.0001), whereas only the posterior DMN component showed reduced connectivity (p1⁄40.047, Figure). Connectivity was significantly lower in bilateral executive-control, language and higher visual networks compared to the DMN components in the AD patients (p<0.05). Looking at specific AD variants, connectivity was reduced in the bilateral executive-control, language and higher visual networks in EO-AD, lvPPA and PCA compared with controls (Figure). The posterior DMN showed a trend for reduced connectivity in EO-AD only (p1⁄40.07). No significant differences were found for the anterior and ventral DMN components. Comparing connectivity between AD variants revealed a trend towards lower connectivity in the higher visual network in PCA compared with lvPPA (p1⁄40.06). Conclusions: Functional networks outside the DMN were strongly affected in early-onset and non-amnestic AD variants, whereas the DMN was less affected, with only the posterior component showing reduced connectivity in the amnestic/dysexecutive variant. Connectivity in networks outside the DMN may represent a better biomarker in early-onset AD variants.