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1.  Patterns of longitudinal brain atrophy in the logopenic variant of primary progressive aphasia 
Brain and Language  2013;127(2):121-126.
Highlights
► Patterns of cell loss in lvPPA remain asymmetrical over time. ► More anterior left hemisphere areas become involved over time. ► Right hemisphere regions become affected that mirror early left hemisphere change. ► Left hemisphere atrophy rates are greater than right hemisphere. ► Over time patients with lvPPA develop single word level processing deficits.
The logopenic variant of primary progressive aphasia (PPA) is characterised by impaired sentence repetition and word retrieval difficulties. Post mortem studies, amyloid imaging and CSF tau/Aβ measurements suggest Alzheimer’s disease (AD) pathology as the underlying cause. Relatively little is known about patterns of progression in patients with the logopenic variant of PPA. 21 patients (3 with post mortem confirmation of AD and 5 with positive amyloid PIB-PET scans) were studied with longitudinal T1-weighted MR imaging (mean interscan interval 1.2 years) using volumetric analysis and voxel-based morphometry (VBM). Baseline imaging showed asymmetrical (left greater than right) involvement of the posterior superior temporal and inferior parietal lobes as well as posterior cingulate and medial temporal lobes. The whole brain rate of volume loss was 2.0% per year with a greater rate of left hemisphere atrophy (2.3%/year) than right hemisphere (1.6%/year). Longitudinal VBM analysis showed increasing involvement of other areas in the left hemisphere (temporal, parietal, frontal and caudate) and atrophy of areas in the right hemisphere that had been involved earlier in the disease in the left hemisphere, particularly posterior cingulate/precuneus. With disease progression there was worsening of anomia, sentence repetition and sentence comprehension but consistent with the spread of imaging changes also deficits in single word comprehension, single word repetition and verbal memory. This study shows that the logopenic variant of PPA remains an asymmetrical disease, with spread through the left hemisphere language network but also involvement to a lesser degree of regions in the right hemisphere that mirror the earlier left hemisphere changes.
doi:10.1016/j.bandl.2012.12.008
PMCID: PMC3880853  PMID: 23395096
Primary progressive aphasia; Logopenic aphasia
2.  Molecular nexopathies: a new paradigm of neurodegenerative disease 
Trends in Neurosciences  2013;36(10):561-569.
Highlights
•How proteinopathies damage brain networks is a key issue in neurodegenerative disease.•Here, we outline a solution based on the concept of ‘molecular nexopathies’.•The concept is founded on specific interactions of network and protein properties.•This new paradigm has far-reaching biological and clinical implications.
Neural networks provide candidate substrates for the spread of proteinopathies causing neurodegeneration, and emerging data suggest that macroscopic signatures of network disintegration differentiate diseases. However, how do protein abnormalities produce network signatures? The answer may lie with ‘molecular nexopathies’: specific, coherent conjunctions of pathogenic protein and intrinsic network characteristics that define network signatures of neurodegenerative pathologies. Key features of the paradigm that we propose here include differential intrinsic network vulnerability to propagating protein abnormalities, in part reflecting developmental structural and functional factors; differential vulnerability of neural connection types (e.g., clustered versus distributed connections) to particular pathogenic proteins; and differential impact of molecular effects (e.g., toxic-gain-of-function versus loss-of-function) on gradients of network damage. The paradigm has implications for understanding and predicting neurodegenerative disease biology.
doi:10.1016/j.tins.2013.06.007
PMCID: PMC3794159  PMID: 23876425
neurodegeneration; dementia; neural network; nexopathy
3.  A novel A781V mutation in the CSF1R gene causes hereditary diffuse leucoencephalopathy with axonal spheroids☆ 
Journal of the Neurological Sciences  2013;332(1-2):141-144.
We report a family with a novel CSF1R mutation causing hereditary diffuse leucoencephalopathy with axonal spheroids. Family members presented with neuropsychiatric and behavioural symptoms, with subsequent development of motor symptoms and gait disturbance. MRI brain showed extensive white matter change with a frontal predominance and associated atrophy in two members of the family. Genetic testing revealed a novel mutation c.2342C > T (p.A781V) in the CSF1R gene in two brothers of the family. This report highlights the difficulties in diagnosing HDLS and discusses the indications for testing for mutations in the CSF1R gene.
doi:10.1016/j.jns.2013.06.007
PMCID: PMC3750216  PMID: 23816250
CSF1R; HDLS; Leucoencephalopathy; Dementia; Frontal dementia; Behavioural change
4.  Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia 
Acta Neuropathologica  2013;126:401-409.
An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43-positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of-function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1147-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s00401-013-1147-0
PMCID: PMC3753468  PMID: 23818065
C9orf72; ALS; FTD
6.  A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies 
Brain  2011;134(9):2548-2564.
Neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration are rare diseases characterized by ubiquitin-positive inclusions lacking transactive response DNA-binding protein-43 and tau. Recently, mutations in the fused in sarcoma gene have been shown to cause familial amyotrophic lateral sclerosis and fused in sarcoma-positive neuronal inclusions have subsequently been demonstrated in neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration with ubiquitinated inclusions. Here we provide clinical, imaging, morphological findings, as well as genetic and biochemical data in 14 fused in sarcoma proteinopathy cases. In this cohort, the age of onset was variable but included cases of young-onset disease. Patients with atypical frontotemporal lobar degeneration with ubiquitinated inclusions all presented with behavioural variant frontotemporal dementia, while the clinical presentation in neuronal intermediate filament inclusion disease was more heterogeneous, including cases with motor neuron disease and extrapyramidal syndromes. Neuroimaging revealed atrophy of the frontal and anterior temporal lobes as well as the caudate in the cases with atypical frontotemporal lobar degeneration with ubiquitinated inclusions, but was more heterogeneous in the cases with neuronal intermediate filament inclusion disease, often being normal to visual inspection early on in the disease. The distribution and severity of fused in sarcoma-positive neuronal cytoplasmic inclusions, neuronal intranuclear inclusions and neurites were recorded and fused in sarcoma was biochemically analysed in both subgroups. Fused in sarcoma-positive neuronal cytoplasmic and intranuclear inclusions were found in the hippocampal granule cell layer in variable numbers. Cortical fused in sarcoma-positive neuronal cytoplasmic inclusions were often ‘Pick body-like’ in neuronal intermediate filament inclusion disease, and annular and crescent-shaped inclusions were seen in both conditions. Motor neurons contained variable numbers of compact, granular or skein-like cytoplasmic inclusions in all fused in sarcoma-positive cases in which brainstem and spinal cord motor neurons were available for study (five and four cases, respectively). No fused in sarcoma mutations were found in any cases. Biochemically, two major fused in sarcoma species were found and shown to be more insoluble in the atypical frontotemporal lobar degeneration with ubiquitinated inclusions subgroup compared with neuronal intermediate filament inclusion disease. There is considerable overlap and also significant differences in fused in sarcoma-positive pathology between the two subgroups, suggesting they may represent a spectrum of the same disease. The co-existence of fused in sarcoma-positive inclusions in both motor neurons and extramotor cerebral structures is a characteristic finding in sporadic fused in sarcoma proteinopathies, indicating a multisystem disorder.
doi:10.1093/brain/awr160
PMCID: PMC3170529  PMID: 21752791
frontotemporal lobar degeneration; FUS; clinical presentation; neuropathology; biochemistry
7.  The MAPT p.A152T variant is a risk factor associated with tauopathies with atypical clinical and neuropathological features 
Neurobiology of Aging  2012;33(9):2231.e7-2231.e14.
Microtubule-associated protein tau (MAPT) mutations have been shown to underlie frontotemporal dementia and a variety of additional sporadic tauopathies. We identified a rare p.A152T variant in MAPT exon 7 in two (of eight) patients with clinical presentation of parkinsonism and postmortem finding of neurofibrillary tangle pathology. Two siblings of one patient also carried the p.A152T variant, and both have progressive cognitive impairment. Further screening identified the variant in two other cases: one with pathologically confirmed corticobasal degeneration and another with the diagnosis of Parkinson's disease with dementia. The balance of evidence suggests this variant is associated with disease, but the very varied phenotype of the cases with the mutation is not consistent with it being a fully penetrant pathogenic mutation. Interestingly, this variation results in the creation of a new phosphorylation site that could cause reduced microtubule binding. We suggest that the A152T variant is a risk factor associated with the development of atypical neurodegenerative conditions with abnormal tau accumulation.
doi:10.1016/j.neurobiolaging.2012.04.006
PMCID: PMC3657164  PMID: 22595371
MAPT; Parkinsonism; Corticobasal degeneration; Genetics; Postencephalitic parkinsonism
8.  Alzheimer's pathology in primary progressive aphasia 
Neurobiology of Aging  2012;33(4-2):744-752.
Primary progressive aphasia (PPA) is a neurodegenerative disorder with language impairment as the primary feature. Different subtypes have been described and the 3 best characterized are progressive nonfluent aphasia (PNFA), semantic dementia (SD) and logopenic/phonological aphasia (LPA). Of these subtypes, LPA is most commonly associated with Alzheimer's disease (AD) pathology. However, the features of PPA associated with AD have not been fully defined. Here we retrospectively identified 14 patients with PPA and either pathologically confirmed AD or cerebrospinal fluid (CSF) biomarkers consistent with AD. Analysis of neurological and neuropsychological features revealed that all patients had a syndrome of LPA with relatively nonfluent spontaneous speech, phonemic errors, and reduced digit span; most patients also had impaired verbal episodic memory. Analysis of the pattern of cortical thinning in these patients revealed left posterior superior temporal, inferior parietal, medial temporal, and posterior cingulate involvement and in patients with more severe disease, increasing involvement of left anterior temporal and frontal cortices and right hemisphere areas in the temporo-parietal junction, posterior cingulate, and medial temporal lobe. We propose that LPA may be a “unihemispheric” presentation of AD, and discuss this concept in relation to accumulating evidence concerning language dysfunction in AD.
doi:10.1016/j.neurobiolaging.2010.05.020
PMCID: PMC3314936  PMID: 20580129
Frontotemporal dementia; Frontotemporal lobar degeneration; Primary progressive aphasia; Logopenic aphasia; Progressive nonfluent aphasia; Alzheimer's disease
9.  Disintegrating Brain Networks: from Syndromes to Molecular Nexopathies 
Neuron  2012;73(6):1060-1062.
In this issue of Neuron, Raj et al. (2012) and Zhou et al. (2012) use graph theory to suggest that neurodegenerative diseases spread diffusively via intrinsic brain networks. These studies provide a powerful model for understanding and predicting disease-specific profiles of neurodegeneration.
doi:10.1016/j.neuron.2012.03.006
PMCID: PMC3389343  PMID: 22445334
10.  Novel L284R MAPT Mutation in a Family with an Autosomal Dominant Progressive Supranuclear Palsy Syndrome 
Neuro-Degenerative Diseases  2010;8(3):149-152.
Background
MAPT mutations are associated with disorders within the frontotemporal lobar degeneration spectrum. The usual presenting syndrome is behavioural variant frontotemporal dementia, although some patients present with parkinsonism. In a number of these cases the dominant clinical features have been consistent with a progressive supranuclear palsy (PSP) syndrome.
Objective
To describe a family with an autosomal dominant PSP syndrome with a novel L284R mutation in the MAPT gene.
Methods
A retrospective case review and genetic analysis of the MAPT gene. A literature review of PSP syndromes associated with mutations in the MAPT gene.
Results
Multiple members of family DRC292 across different generations had a PSP syndrome with 1 member of the family being found to have a novel L284R mutation in the MAPT gene. Behavioural features were also prominent in most cases. A PSP syndrome is only a rare finding associated with MAPT mutations and many of these cases have atypical clinical features.
Conclusion
Although rare, MAPT mutations should be considered when there is an autosomal dominant family history of a PSP syndrome, particularly of young onset and with prominent behavioural features.
doi:10.1159/000319454
PMCID: PMC3078284  PMID: 20838030
Frontotemporal dementia; Progressive supranuclear palsy; Tau
11.  Receptive prosody in nonfluent primary progressive aphasias 
Introduction
Prosody has been little studied in the primary progressive aphasias (PPAs), a group of neurodegenerative disorders presenting with progressive language impairment.
Methods
Here we conducted a systematic investigation of different dimensions of prosody processing (acoustic, linguistic and emotional) in a cohort of 19 patients with nonfluent PPA syndromes (11 with progressive nonfluent aphasia, PNFA; five with progressive logopenic/phonological aphasia, LPA; three with progranulin-associated aphasia, GRN-PPA) compared with a group of healthy older controls. Voxel-based morphometry (VBM) was used to identify neuroanatomical associations of prosodic functions.
Results
Broadly comparable receptive prosodic deficits were exhibited by the PNFA, LPA and GRN-PPA subgroups, for acoustic, linguistic and affective dimensions of prosodic analysis. Discrimination of prosodic contours was significantly more impaired than discrimination of simple acoustic cues, and discrimination of intonation was significantly more impaired than discrimination of stress at phrasal level. Recognition of vocal emotions was more impaired than recognition of facial expressions for the PPA cohort, and recognition of certain emotions (in particular, disgust and fear) was relatively more impaired than others (sadness, surprise). VBM revealed atrophy associated with acoustic and linguistic prosody impairments in a distributed cortical network including areas likely to be involved in perceptual analysis of vocalisations (posterior temporal and inferior parietal cortices) and working memory (fronto-parietal circuitry). Grey matter associations of emotional prosody processing were identified for negative emotions (disgust, fear, sadness) in a broadly overlapping network of frontal, temporal, limbic and parietal areas.
Conclusions
Taken together, the findings show that receptive prosody is impaired in nonfluent PPA syndromes, and suggest a generic early perceptual deficit of prosodic signal analysis with additional relatively specific deficits (recognition of particular vocal emotions).
doi:10.1016/j.cortex.2010.09.004
PMCID: PMC3275751  PMID: 21047627
Primary progressive aphasia; Frontotemporal dementia; Frontotemporal lobar degeneration; Logopenic aphasia; Progranulin; Prosody
12.  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
13.  Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration 
Brain  2011;134(9):2565-2581.
Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.
doi:10.1093/brain/awr198
PMCID: PMC3170537  PMID: 21908872
frontotemporal dementia; frontotemporal lobar degeneration; voxel-based morphometry; MRI; neural network
14.  Syndromes of nonfluent primary progressive aphasia 
Neurology  2010;75(7):603-610.
Background:
Despite recent work, the nosology of nonfluent primary progressive aphasia (PPA) remains unresolved.
Methods:
We describe a clinical and neurolinguistic cross-sectional analysis of a cohort of 24 patients with nonfluent PPA. Patients were initially classified based on analysis of spontaneous speech into 4 groups: apraxia of speech (AOS)/agrammatism (10 patients); AOS/no agrammatism (4 patients); no AOS/agrammatism (3 patients); no AOS/no agrammatism (7 patients). These groups were further characterized using a detailed neurolinguistic and neuropsychological battery. Parkinsonism was present in 3/10 patients in the AOS/agrammatism group. All patients in the no AOS/agrammatism group had mutations in the progranulin (GRN) gene, while 5/7 cases in the no AOS/no agrammatism group had CSF findings compatible with Alzheimer disease.
Results:
The groups without AOS showed more severe neurolinguistic impairments for a given disease stage, and sentence comprehension, speech repetition, and reading were impaired in all groups. Prolonged word-finding pauses and impaired single word comprehension were salient features in the no AOS/agrammatism group. Additional impairments of executive function and praxis were present in both groups with agrammatism, and impaired episodic memory was a feature of the no AOS/no agrammatism group.
Conclusion:
PPA with AOS is aligned with the syndrome previously designated progressive nonfluent aphasia; agrammatism may emerge as the syndrome evolves, or alternatively, the pure AOS group may be pathophysiologically distinct. PPA without AOS resembles the syndrome designated logopenic/phonologic aphasia; however, there is evidence for a distinct subsyndrome of GRN-associated aphasia. The findings provide a rationale for further longitudinal studies with pathologic correlation.
GLOSSARY
= Alzheimer disease;
= apraxia of speech;
= Clinical Dementia Rating–sum of boxes;
= logopenic progressive aphasia;
= Mini-Mental State Examination score;
= progressive nonfluent aphasia;
= primary progressive aphasia;
= semantic dementia.
doi:10.1212/WNL.0b013e3181ed9c6b
PMCID: PMC2931766  PMID: 20713949
15.  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
16.  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
17.  Structural neuroanatomy of face processing in frontotemporal lobar degeneration 
Impairments of face processing occur frequently in frontotemporal lobar degeneration (FTLD) but the neuroanatomical basis for these deficits has seldom been studied systematically. Here a prospective voxel based morphometry study is described addressing the neuroanatomy of two key dimensions of face processing—face identification and facial emotion recognition—in a single cohort of 32 patients with FTLD (19 with frontal variant and 13 with temporal variant FTLD). For the FTLD group as a whole, face identification was positively associated with grey matter in the right anterior fusiform gyrus while recognition of angry expressions was positively associated with grey matter in the bilateral insula cortex. FTLD provides a perspective on the neuroanatomy of face processing that is complementary to focal lesion and normal functional imaging work.
doi:10.1136/jnnp.2010.227983
PMCID: PMC3212647  PMID: 21172863
Ffaces; emotion; voxel-based morphometry; frontotemporal lobar degeneration; dementia; cognitive neuropsychology; dementia; image analysis; MRI; neuroanatomy
18.  Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations☆ 
Neuroimage  2010;53(3-3):1070-1076.
Neural network breakdown is a key issue in neurodegenerative disease, but the mechanisms are poorly understood. Here we investigated patterns of brain atrophy produced by defined molecular lesions in the two common forms of genetically mediated frontotemporal lobar degeneration (FTLD). Nine patients with progranulin (GRN) mutations and eleven patients with microtubule-associated protein tau (MAPT) mutations had T1 MR brain imaging. Brain volumetry and grey and white matter voxel-based morphometry (VBM) were used to assess patterns of cross-sectional atrophy in the two groups. In a subset of patients with longitudinal MRI rates of whole-brain atrophy were derived using the brain-boundary-shift integral and a VBM-like analysis of voxel-wise longitudinal volume change was performed. The GRN mutation group showed asymmetrical atrophy whereas the MAPT group showed symmetrical atrophy. Brain volumes were smaller in the GRN group with a faster rate of whole-brain atrophy. VBM delineated a common anterior cingulate–prefrontal–insular pattern of atrophy in both disease groups. Additional disease-specific profiles of grey and white matter loss were identified on both cross-sectional and longitudinal imaging: GRN mutations were associated with asymmetrical inferior frontal, temporal and inferior parietal lobe grey matter atrophy and involvement of long intrahemispheric association white matter tracts, whereas MAPT mutations were associated with symmetrical anteromedial temporal lobe and orbitofrontal grey matter atrophy and fornix involvement. The findings suggest that the effects of GRN and MAPT mutations are expressed in partly overlapping but distinct anatomical networks that link specific molecular dysfunction with clinical phenotype.
doi:10.1016/j.neuroimage.2009.12.088
PMCID: PMC2941039  PMID: 20045477
Frontotemporal dementia; Frontotemporal lobar degeneration; Progranulin; Tau
19.  FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration 
Acta neuropathologica  2010;120(1):33-41.
Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.
doi:10.1007/s00401-010-0698-6
PMCID: PMC2887939  PMID: 20490813
FTLD; FUS; FTLD-UPS; Frontotemporal; FTD
20.  Phenomenology and anatomy of abnormal behaviours in primary progressive aphasia 
Primary progressive aphasia (PPA) is a group of disorders with progressive language impairment. Abnormal behaviour may develop in PPA as the disease evolves, but the clinical features and brain basis of behavioural change in PPA have not been fully defined. 33 PPA patients (9 semantic dementia, SD, 14 progressive nonfluent aphasia, PNFA, 7 logopenic/phonological aphasia, LPA and 3 patients with a PPA syndrome in association with progranulin mutations, GRN-PPA) were assessed using the Neuropsychiatric Inventory to record behavioural changes, as well as volumetric MR imaging. The most common abnormal behaviours in SD were irritability, disinhibition, depression and abnormal appetite, in PNFA apathy, agitation and depression, in LPA anxiety, irritability, agitation and apathy, and in GRN-PPA apathy and irritability. Voxel-based morphometry analysis revealed greater atrophy of right lateral orbitofrontal cortex (OFC) in PPA patients with anxiety, apathy, irritability/lability and abnormal appetite/eating disorders, and greater atrophy of left OFC in those with disinhibition. Areas involved beyond OFC included right dorsolateral prefrontal cortex (apathy), right cingulate (irritability/lability) and left anterior superior and medial temporal lobe (disinhibition). Behavioural abnormalities may be clinically significant in PPA, and these abnormalities are underpinned by atrophy of overlapping frontotemporal networks centred on OFC.
doi:10.1016/j.jns.2010.03.012
PMCID: PMC2896484  PMID: 20400120
Primary progressive aphasia; Frontotemporal lobar degeneration; Frontotemporal dementia
22.  FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration 
Acta Neuropathologica  2010;120(1):33-41.
Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.
doi:10.1007/s00401-010-0698-6
PMCID: PMC2887939  PMID: 20490813
FTLD; FUS; FTLD-UPS; Frontotemporal; FTD
23.  Ubiquitin Associated Protein 1 is a risk factor for frontotemporal lobar degeneration 
Neurobiology of aging  2009;30(4):656-665.
Frontotemporal lobar degeneration (FTLD) is now recognised as a common form of early onset dementia. Up to 40% of patients have a family history of disease demonstrating a large genetic component to its etiology. Linkage to chromosome 9p21 has recently been reported in families with this disorder. We undertook a large scale two-stage linkage disequilibrium mapping approach of this region in the Manchester FTLD cohort. We identified association of ubiquitin-associated-protein-1 (UBAP1; OR 1.42 95% CI 1.08–1.88, P=0.013) with FTLD in this cohort and we replicated this finding in an additional two independent cohorts from the Netherlands (OR 1.33 95% CI 1.04–1.69, P=0.022), the USA (OR 1.4 95% CI 1.02–1.92, P=0.032) and a forth Spainish cohort approached significant association (OR 1.45 95% CI 0.97–2.17, p=0.064). However, we failed to replicate in a fifth cohort from London (OR 0.99 95% CI 0.72–1.37, p=0.989). Quantitative analysis of UBAP1 mRNA extracted from tissue from the Manchester cases demonstrated a significant reduction of expression from the disease-associated haplotype. In addition, we identified a case of familial FTLD that demonstrated colocalisation of UBAP1 and TDP-43 in the neuronal cytoplasmic inclusions in the brain of this individual. Our data for the first time identifies UBAP1 as a genetic risk factor for FTLD and suggests a mechanistic relationship between this protein and TDP-43.
doi:10.1016/j.neurobiolaging.2009.01.009
PMCID: PMC2753870  PMID: 19217189
24.  Progranulin-associated primary progressive aphasia: A distinct phenotype? 
Neuropsychologia  2010;48(1):288-297.
The neuropsychological features of the primary progressive aphasia (PPA) syndromes continue to be defined. Here we describe a detailed neuropsychological case study of a patient with a mutation in the progranulin (GRN) gene who presented with progressive word-finding difficulty. Key neuropsychological features in this case included gravely impoverished propositional speech with anomia and prolonged word-finding pauses, impaired speech repetition most marked for sentences, and severely impaired verbal (with preserved spatial) short-term memory. There was a dissociated profile of performance on semantic processing tasks: visual semantic processing was intact, while within the verbal domain, verb comprehension was impaired and processing of nouns was intact on tasks requiring direct semantic processing but impaired on tasks requiring associative or inferential processing. Brain MRI showed asymmetric left cerebral atrophy particularly affecting the temporo-parietal junction, supero-lateral temporal and inferior frontal lobes. This case most closely resembles the PPA syndrome known as the logopenic/phonological aphasia variant (LPA) however there were also deficits of grammar and speech repetition suggesting an overlap with the progressive non-fluent aphasia (agrammatic) variant (PNFA). Certain prominent features of this case (in particular, the profile of semantic impairment) have not been emphasised in previous descriptions of LPA or PNFA, suggesting that GRN may cause an overlapping PPA syndrome but with a distinctive cognitive profile. This neuropsychological evidence suggests that GRN-PPA may result from damage involving the temporo-parietal junction and its functional connections in both the dorsal and ventral language networks, with implications for our understanding of language network pathophysiology.
doi:10.1016/j.neuropsychologia.2009.09.017
PMCID: PMC2808475  PMID: 19766663
Primary progressive aphasia; Dementia; Progranulin; Aphasia; Language
25.  Progressive logopenic/phonological aphasia: Erosion of the language network 
Neuroimage  2010;49(1):984-993.
The primary progressive aphasias (PPA) are paradigmatic disorders of language network breakdown associated with focal degeneration of the left cerebral hemisphere. Here we addressed brain correlates of PPA in a detailed neuroanatomical analysis of the third canonical syndrome of PPA, logopenic/phonological aphasia (LPA), in relation to the more widely studied clinico-anatomical syndromes of semantic dementia (SD) and progressive nonfluent aphasia (PNFA). 32 PPA patients (9 SD, 14 PNFA, 9 LPA) and 18 cognitively normal controls had volumetric brain MRI with regional volumetry, cortical thickness, grey and white matter voxel-based morphometry analyses. Five of nine patients with LPA had cerebrospinal fluid biomarkers consistent with Alzheimer (AD) pathology (AD-PPA) and 2/9 patients had progranulin (GRN) mutations (GRN-PPA). The LPA group had tissue loss in a widespread left hemisphere network. Compared with PNFA and SD, the LPA group had more extensive involvement of grey matter in posterior temporal and parietal cortices and long association white matter tracts. Overlapping but distinct networks were involved in the AD-PPA and GRN-PPA subgroups, with more anterior temporal lobe involvement in GRN-PPA. The importance of these findings is threefold: firstly, the clinico-anatomical entity of LPA has a profile of brain damage that is complementary to the network-based disorders of SD and PNFA; secondly, the core phonological processing deficit in LPA is likely to arise from temporo-parietal junction damage but disease spread occurs through the dorsal language network (and in GRN-PPA, also the ventral language network); and finally, GRN mutations provide a specific molecular substrate for language network dysfunction.
doi:10.1016/j.neuroimage.2009.08.002
PMCID: PMC2943046  PMID: 19679189
Primary progressive aphasia; Frontotemporal dementia; Frontotemporal lobar degeneration; Logopenic aphasia

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