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1.  The Presenilin 1 P264L mutation presenting as non-fluent/agrammatic primary progressive aphasia 
Primary progressive aphasia (PPA) represents a diverse group of language-led dementias most often due to frontotemporal lobar degeneration. We report clinical, neuropsychological and neuroimaging data in the case of a 47 year old woman presenting with non-fluent PPA due to a genetically confirmed pathogenic Presenilin 1 P264L mutation. This case highlights an unusual clinical presentation of familial Alzheimer’s disease and a novel presentation of the P264L mutation. The case adds to accumulating evidence that particular mutations can promote specific brain network degeneration, with wider implications for understanding the sporadic forms of Alzheimer’s disease and PPA.
doi:10.3233/JAD-122092
PMCID: PMC4041608  PMID: 23579325
Primary progressive aphasia; familial Alzheimer’s disease; Presenilin 1
2.  Mentalising music in frontotemporal dementia 
Despite considerable recent interest, the biological basis and clinical diagnosis of behavioural variant frontotemporal dementia (bvFTD) pose unresolved problems. Mentalising (the cognitive capacity to interpret the behaviour of oneself and others in terms of mental states) is impaired as a prominent feature of bvFTD, consistent with involvement of brain regions including ventro-medial prefrontal cortex (PFC), orbitofrontal cortex and anterior temporal lobes. Here, we investigated mentalising ability in a cohort of patients with bvFTD using a novel modality: music. We constructed a novel neuropsychological battery requiring attribution of affective mental or non-mental associations to musical stimuli. Mentalising performance of patients with bvFTD (n = 20) was assessed in relation to matched healthy control subjects (n = 20); patients also had a comprehensive assessment of behaviour and general neuropsychological functions. Neuroanatomical correlates of performance on the experimental tasks were investigated using voxel-based morphometry of patients' brain magnetic resonance imaging (MRI) scans. Compared to healthy control subjects, patients showed impaired ability to attribute mental states but not non-mental characteristics to music, and this deficit correlated with performance on a standard test of social inference and with carer ratings of patients' empathic capacity, but not with other potentially relevant measures of general neuropsychological function. Mentalising performance in the bvFTD group was associated with grey matter changes in anterior temporal lobe and ventro-medial PFC. These findings suggest that music can represent surrogate mental states and the ability to construct such mental representations is impaired in bvFTD, with potential implications for our understanding of the biology of bvFTD and human social cognition more broadly.
doi:10.1016/j.cortex.2012.09.011
PMCID: PMC3701324  PMID: 23107380
Mentalising; Theory of mind; Music; Frontotemporal dementia
3.  White matter tract signatures of the progressive aphasias 
Neurobiology of Aging  2013;34(6):1687-1699.
The primary progressive aphasias (PPA) are a heterogeneous group of language-led neurodegenerative diseases resulting from large-scale brain network degeneration. White matter (WM) pathways bind networks together, and might therefore hold information about PPA pathogenesis. Here we used diffusion tensor imaging and tract-based spatial statistics to compare WM tract changes between PPA syndromes and with respect to Alzheimer's disease and healthy controls in 33 patients with PPA (13 nonfluent/agrammatic PPA); 10 logopenic variant PPA; and 10 semantic variant PPA. Nonfluent/agrammatic PPA was associated with predominantly left-sided and anterior tract alterations including uncinate fasciculus (UF) and subcortical projections; semantic variant PPA with bilateral alterations in inferior longitudinal fasciculus and UF; and logopenic variant PPA with bilateral but predominantly left-sided alterations in inferior longitudinal fasciculus, UF, superior longitudinal fasciculus, and subcortical projections. Tract alterations were more extensive than gray matter alterations, and the extent of alteration across tracts and PPA syndromes varied between diffusivity metrics. These WM signatures of PPA syndromes illustrate the selective vulnerability of brain language networks in these diseases and might have some pathologic specificity.
doi:10.1016/j.neurobiolaging.2012.12.002
PMCID: PMC3601331  PMID: 23312804
Primary progressive aphasia; DTI; Networks; White matter
4.  Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels 
Neuron  2013;78(1):57-64.
Summary
Valosin-containing protein (VCP) is a highly expressed member of the type II AAA+ ATPase family. VCP mutations are the cause of inclusion body myopathy, Paget’s disease of the bone, and frontotemporal dementia (IBMPFD) and they account for 1%–2% of familial amyotrophic lateral sclerosis (ALS). Using fibroblasts from patients carrying three independent pathogenic mutations in the VCP gene, we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption. This mitochondrial uncoupling results in a significant reduction of cellular ATP production. Decreased ATP levels in VCP-deficient cells lower their energy capacity, making them more vulnerable to high energy-demanding processes such as ischemia. Our findings propose a mechanism by which pathogenic VCP mutations lead to cell death.
Highlights
► VCP deficiency is associated with mitochondrial depolarization ► VCP deficiency leads to increased mitochondrial respiration and uncoupling ► ATP levels are decreased in VCP-deficient cells due to lower ATP production
In this study, Bartolome et al. show that three independent pathogenic VCP mutations induce mitochondrial uncoupling, resulting in low cellular ATP production, rendering the cells more susceptible to cell death under stress-induced ischemic conditions.
doi:10.1016/j.neuron.2013.02.028
PMCID: PMC3843114  PMID: 23498975
5.  Flavour identification in frontotemporal lobar degeneration 
Background
Deficits of flavour processing may be clinically important in frontotemporal lobar degeneration (FTLD).
Objective
To examine  flavour processing in FTLD.
Methods
We studied flavour identification prospectively in 25 patients with FTLD (12 with behavioural variant frontotemporal dementia (bvFTD), eight with semantic variant primary progressive aphasia (svPPA), five with non-fluent variant primary progressive aphasia (nfvPPA)) and 17 healthy control subjects, using a new test based on cross-modal matching of flavours to words and pictures. All subjects completed a general neuropsychological assessment, and odour identification was also assessed using a modified University of Pennsylvania Smell Identification Test. Brain MRI volumes from the patient cohort were analysed using voxel-based morphometry to identify regional grey matter associations of flavour identification.
Results
Relative to the healthy control group, the bvFTD and svPPA subgroups showed significant (p<0.05) deficits of flavour identification and all three FTLD subgroups showed deficits of odour identification. Flavour identification performance did not differ significantly between the FTLD syndromic subgroups. Flavour identification performance in the combined FTLD cohort was significantly (p<0.05 after multiple comparisons correction) associated with grey matter volume in the left entorhinal cortex, hippocampus, parahippocampal gyrus and temporal pole.
Conclusions
Certain FTLD syndromes are associated with impaired flavour identification and this is underpinned by grey matter atrophy in an anteromedial temporal lobe network. These findings may have implications for our understanding of abnormal eating behaviour in these diseases.
doi:10.1136/jnnp-2012-303853
PMCID: PMC3534254  PMID: 23138765
Cognition; Dementia; Neuropsychology; MRI; Neuroanatomy
6.  Longitudinal neuroimaging and neuropsychological profiles of frontotemporal dementia with C9ORF72 expansions 
Introduction
Frontotemporal dementia (FTD) is a common cause of early-onset dementia with a significant genetic component, as underlined by the recent identification of repeat expansions in the gene C9ORF72 as a major cause of FTD and motor neuron disease. Understanding the neurobiology and clinical phenomenology of this novel mutation is currently a major research focus. However, few data are available concerning the longitudinal evolution of this genetic disease. Here we present longitudinal neuropsychological and neuroimaging data on a cohort of patients with pathological repeat expansions in C9ORF72.
Methods
Following a review of the University College London FTD DNA database, 20 cases were retrospectively identified with a C9ORF72 expansion. Twelve cases had longitudinal neuropsychology data available and six of these cases also had longitudinal volumetric brain magnetic resonance imaging. Cortical and subcortical volumes were extracted using FreeSurfer. Rates of whole brain, hemispheric, cerebellar and ventricular change were calculated for each subject. Nonlinear fluid registration of follow-up to baseline scan was performed to visualise longitudinal intra-subject patterns of brain atrophy and ventricular expansion.
Results
Patients had low average verbal and performance IQ at baseline that became impaired (< 5th percentile) at follow-up. In particular, visual memory, naming and dominant parietal skills all showed deterioration. Mean rates of whole brain atrophy (1.4%/year) and ventricular expansion (3.2 ml/year) were substantially greater in patients with the C9ORF72 mutation than in healthy controls; atrophy was symmetrical between the cerebral hemispheres within the C9ORF72 mutation group. The thalamus and cerebellum showed significant atrophy whereas no cortical areas were preferentially affected. Longitudinal fluid imaging in individual patients demonstrated heterogeneous patterns of progressive volume loss; however, ventricular expansion and cerebellar volume loss were consistent findings.
Conclusion
Disease evolution in C9ORF72-associated FTD is linked neuropsychologically with increasing involvement of parietal and amnestic functions, and neuroanatomically with rather diffuse and variable cortical and central atrophy but more consistent involvement of the cerebellum and thalamus. These longitudinal profiles are consistent with disease spread within a distributed subcortical network and demonstrate the feasibility of longitudinal biomarkers for tracking the evolution of the C9ORF72 mutation phenotype.
doi:10.1186/alzrt144
PMCID: PMC3580398  PMID: 23006986
7.  Impaired self-other differentiation in frontotemporal dementia due to the C9ORF72 expansion 
Introduction
An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as an important cause of frontotemporal dementia and motor neuron disease; however, the phenotypic spectrum of this entity and its pathophysiologic basis have yet to be fully defined. Psychiatric features may be early and prominent, although a putative cortico-thalamo-cerebellar network has been implicated in the pathogenesis of the clinical phenotype. Differentiation of self from others is a core cognitive operation that could potentially link network disintegration with neuropsychiatric symptoms in C9ORF72-associated frontotemporal dementia.
Methods
We undertook a detailed behavioral analysis of self-other attribution in a 67-year-old male patient with behavioral variant frontotemporal dementia (bvFTD) due to the C9ORF72 expansion by using a novel paradigm requiring differentiation of the effects of self- and non-self-generated actions. The patient's performance was assessed in relation to two older male patients with bvFTD not attributable to the C9ORF72 expansion and four healthy older male subjects.
Results
Compared with the healthy control group, the patient with the C9OFR72 mutation showed a deficit of self-other differentiation that was disproportionate to his otherwise relatively indolent clinical phenotype. The performance of the other patients with bvFTD was similar to that of healthy subjects.
Conclusion
We propose that impaired self-other differentiation is a candidate mechanism for neuropsychiatric decline in association with the C9ORF72 expansion. We offer this preliminary observation as a stimulus to further work.
doi:10.1186/alzrt145
PMCID: PMC3580399  PMID: 23016833
8.  Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features 
Brain  2012;135(3):736-750.
An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43–68 years) and duration (1.7–22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases with C9ORF72 mutation from the frontotemporal lobar degeneration series identified histomorphological features consistent with either type A or B TAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR DNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus and cerebellum were a consistent feature of these cases, in contrast to the similar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control cases with frontotemporal lobar degeneration–TAR DNA-binding protein. These findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.
doi:10.1093/brain/awr361
PMCID: PMC3286330  PMID: 22366791
frontotemporal lobar degeneration; motor neuron disease; neurodegenerative disorders; neuroimaging; genetics
9.  Neuroanatomical profiles of personality change in frontotemporal lobar degeneration 
The British Journal of Psychiatry  2011;198(5):365-372.
Background
The neurobiological basis of personality is poorly understood. Frontotemporal lobar degeneration (FTLD) frequently presents with complex behavioural changes, and therefore potentially provides a disease model in which to investigate brain substrates of personality.
Aims
To assess neuroanatomical correlates of personality change in a cohort of individuals with FTLD using voxel-based morphometry (VBM).
Method
Thirty consecutive individuals fulfilling consensus criteria for FTLD were assessed. Each participant’s carer completed a Big Five Inventory (BFI) questionnaire on five key personality traits; for each trait, a change score was derived based on current compared with estimated premorbid characteristics. All participants underwent volumetric brain magnetic resonance imaging. A VBM analysis was implemented regressing change score for each trait against regional grey matter volume across the FTLD group.
Results
The FTLD group showed a significant decline in extraversion, agreeableness, conscientiousness and openness and an increase in neuroticism. Change in particular personality traits was associated with overlapping profiles of grey matter loss in more anterior cortical areas and relative preservation of grey matter in more posterior areas; the most robust neuroanatomical correlate was identified for reduced conscientiousness in the region of the posterior superior temporal gyrus.
Conclusions
Quantitative measures of personality change in FTLD can be correlated with changes in regional grey matter. The neuroanatomical profiles for particular personality traits overlap brain circuits previously implicated in aspects of social cognition and suggest that dysfunction at the level of distributed cortical networks underpins personality change in FTLD.
doi:10.1192/bjp.bp.110.082677
PMCID: PMC3093679  PMID: 21372059
10.  Structural neuroanatomy of tinnitus and hyperacusis in semantic dementia 
Introduction
Tinnitus and hyperacusis are common symptoms of excessive auditory perception in the general population; however, their anatomical substrates and disease associations continue to be defined. Patients with semantic dementia (SemD) frequently report tinnitus and hyperacusis but the significance and basis for these symptoms have not been elucidated.
Methods
43 patients with a diagnosis of SemD attending a specialist cognitive disorders clinic were retrospectively studied. 14 patients (32% of the cohort) reported at least moderately severe chronic auditory symptoms: seven had tinnitus and a further seven had hyperacusis, and all had brain MRI while symptomatic. MRI data from SemD patients with and without auditory symptoms were compared using voxel based morphometry in order to identify neuroanatomical associations of tinnitus and hyperacusis.
Results
Compared with SemD patients with no history of auditory symptoms, patients with tinnitus or hyperacusis had relative preservation of grey matter in the posterior superior temporal lobe and reduced grey matter in the orbitofrontal cortex and medial geniculate nucleus.
Conclusions
Tinnitus and hyperacusis may be a significant issue in SemD. Neuroanatomical evidence in SemD supports previous work implicating a distributed cortico-subcortical auditory and limbic network in the pathogenesis of these abnormal auditory percepts.
doi:10.1136/jnnp.2010.235473
PMCID: PMC3188784  PMID: 21531705
11.  Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research 
PLoS ONE  2012;7(8):e43099.
Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
doi:10.1371/journal.pone.0043099
PMCID: PMC3428297  PMID: 22952635

Results 1-11 (11)