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1.  “The Mind Is Its Own Place”: Amelioration of Claustrophobia in Semantic Dementia 
Behavioural Neurology  2014;2014:584893.
Phobias are among the few intensely fearful experiences we regularly have in our everyday lives, yet the brain basis of phobic responses remains incompletely understood. Here we describe the case of a 71-year-old patient with a typical clinicoanatomical syndrome of semantic dementia led by selective (predominantly right-sided) temporal lobe atrophy, who showed striking amelioration of previously disabling claustrophobia following onset of her cognitive syndrome. We interpret our patient's newfound fearlessness as an interaction of damaged limbic and autonomic responsivity with loss of the cognitive meaning of previously threatening situations. This case has implications for our understanding of brain network disintegration in semantic dementia and the neurocognitive basis of phobias more generally.
doi:10.1155/2014/584893
PMCID: PMC4006598  PMID: 24825962
2.  Delayed auditory feedback simulates features of nonfluent primary progressive aphasia 
Journal of the Neurological Sciences  2014;347(1-2):345-348.
The pathophysiology of nonfluent primary progressive aphasia (nfvPPA) remains poorly understood. Here, we compared quantitatively speech parameters in patients with nfvPPA versus healthy older individuals under altered auditory feedback, which has been shown to modulate normal speech output. Patients (n = 15) and healthy volunteers (n = 17) were recorded while reading aloud under delayed auditory feedback [DAF] with latency 0, 50 or 200 ms and under DAF at 200 ms plus 0.5 octave upward pitch shift. DAF in healthy older individuals was associated with reduced speech rate and emergence of speech sound errors, particularly at latency 200 ms. Up to a third of the healthy older group under DAF showed speech slowing and frequency of speech sound errors within the range of the nfvPPA cohort. Our findings suggest that (in addition to any anterior, primary language output disorder) these key features of nfvPPA may reflect distorted speech input signal processing, as simulated by DAF. DAF may constitute a novel candidate pathophysiological model of posterior dorsal cortical language pathway dysfunction in nfvPPA.
Highlights
•The pathophysiology of nonfluent progressive aphasia (nfvPPA) is poorly understood.•Delayed auditory feedback (DAF) disrupts speech output in some normal listeners.•We compared quantitatively speech in nvfPPA with DAF in healthy older individuals.•Around a third of healthy older individuals under DAF developed features of nvfPPA.•DAF is a candidate pathophysiological model of dorsal pathway dysfunction in nfvPPA.
doi:10.1016/j.jns.2014.09.039
PMCID: PMC4267508  PMID: 25305712
Delayed auditory feedback; Altered auditory feedback; Dementia; Progressive aphasia; Language; Dorsal pathway
3.  Prominent effects and neural correlates of visual crowding in a neurodegenerative disease population 
Brain  2014;137(12):3284-3299.
Visual crowding is a perceptual phenomenon whereby recognition of a stimulus is disrupted by the presence of flanker stimuli. Yong et al. observe excessive crowding in individuals with a neurodegenerative condition (posterior cortical atrophy) and identify associations between prominent crowding and lower grey matter volume in the right collateral sulcus.
Crowding is a breakdown in the ability to identify objects in clutter, and is a major constraint on object recognition. Crowding particularly impairs object perception in peripheral, amblyopic and possibly developing vision. Here we argue that crowding is also a critical factor limiting object perception in central vision of individuals with neurodegeneration of the occipital cortices. In the current study, individuals with posterior cortical atrophy (n = 26), typical Alzheimer’s disease (n = 17) and healthy control subjects (n = 14) completed centrally-presented tests of letter identification under six different flanking conditions (unflanked, and with letter, shape, number, same polarity and reverse polarity flankers) with two different target-flanker spacings (condensed, spaced). Patients with posterior cortical atrophy were significantly less accurate and slower to identify targets in the condensed than spaced condition even when the target letters were surrounded by flankers of a different category. Importantly, this spacing effect was observed for same, but not reverse, polarity flankers. The difference in accuracy between spaced and condensed stimuli was significantly associated with lower grey matter volume in the right collateral sulcus, in a region lying between the fusiform and lingual gyri. Detailed error analysis also revealed that similarity between the error response and the averaged target and flanker stimuli (but not individual target or flanker stimuli) was a significant predictor of error rate, more consistent with averaging than substitution accounts of crowding. Our findings suggest that crowding in posterior cortical atrophy can be regarded as a pre-attentive process that uses averaging to regularize the pathologically noisy representation of letter feature position in central vision. These results also help to clarify the cortical localization of feature integration components of crowding. More broadly, we suggest that posterior cortical atrophy provides a neurodegenerative disease model for exploring the basis of crowding. These data have significant implications for patients with, or who will go on to develop, dementia-related visual impairment, in whom acquired excessive crowding likely contributes to deficits in word, object, face and scene perception.
doi:10.1093/brain/awu293
PMCID: PMC4240300  PMID: 25351740
crowding; lateral masking; Alzheimer’s disease; posterior cortical atrophy; acquired dyslexia
4.  Genetic Analysis of Inherited Leukodystrophies 
JAMA neurology  2013;70(7):875-882.
Importance
The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. Recently, Rademakers and colleagues identified mutations in the CSF1R gene as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), offering the possibility for an in-life diagnosis. The detection of mutations in this gene in cases diagnosed with different clinical entities further demonstrated the difficulties in the clinical diagnosis of HDLS.
Objective
To better understand the genetic role of mutations in this gene, we sequenced a large cohort of adult-onset leukodystrophy cases.
Design
Whole-exome sequencing and follow up-screening by Sanger sequencing.
Setting
Collaborative study between the Institute of Neurology, University College London and the Inserm, Paris, France.
Participants
A total of 114 probands, mostly European patients, with a diagnosis of adult-onset leukodystrophy or atypical cases that could fit within a picture of leukodystrophy. These included 3 extended families within the spectrum of leukodystrophy phenotype.
Interventions
Whole-exome sequencing in a family and Sanger sequencing of CSF1R.
Main Outcomes and Measures
Mutations in CSF1R.
Results
We identified 12 probands with mutations in CSF1R. The clinical diagnoses given to these patients included dementia with spastic paraplegia, corticobasal degeneration syndrome, and stroke disorders. Our study shows that CSF1R mutations are responsible for a significant proportion of clinically and pathologically proven HDLS.
Conclusions and Relevance
These results give an indication of the frequency of CSF1R mutations in a European leukodystrophy series and expand the phenotypic spectrum of disorders that should be screened for this gene.
doi:10.1001/jamaneurol.2013.698
PMCID: PMC4204151  PMID: 23649896
5.  The brain basis of musicophilia: evidence from frontotemporal lobar degeneration 
Musicophilia, or abnormal craving for music, is a poorly understood phenomenon that has been associated in particular with focal degeneration of the temporal lobes. Here we addressed the brain basis of musicophilia using voxel-based morphometry (VBM) on MR volumetric brain images in a retrospectively ascertained cohort of patients meeting clinical consensus criteria for frontotemporal lobar degeneration: of 37 cases ascertained, 12 had musicophilia, and 25 did not exhibit the phenomenon. The syndrome of semantic dementia was relatively over-represented among the musicophilic subgroup. A VBM analysis revealed significantly increased regional gray matter volume in left posterior hippocampus in the musicophilic subgroup relative to the non-musicophilic group (p < 0.05 corrected for regional comparisons); at a relaxed significance threshold (p < 0.001 uncorrected across the brain volume) musicophilia was associated with additional relative sparing of regional gray matter in other temporal lobe and prefrontal areas and atrophy of gray matter in posterior parietal and orbitofrontal areas. The present findings suggest a candidate brain substrate for musicophilia as a signature of distributed network damage that may reflect a shift of hedonic processing toward more abstract (non-social) stimuli, with some specificity for particular neurodegenerative pathologies.
doi:10.3389/fpsyg.2013.00347
PMCID: PMC3689257  PMID: 23801975
music; musicophilia; craving; frontotemporal dementia; degeneration
6.  Olfactory impairment in posterior cortical atrophy 
doi:10.1136/jnnp-2012-304497
PMCID: PMC3623030  PMID: 23435114
Smell; Psychology, Experimental; Dementia; Alzheimer's Disease; MRI
7.  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
8.  (Con)text-specific effects of visual dysfunction on reading in posterior cortical atrophy 
Reading deficits are a common early feature of the degenerative syndrome posterior cortical atrophy (PCA) but are poorly understood even at the single word level. The current study evaluated the reading accuracy and speed of 26 PCA patients, 17 typical Alzheimer's disease (tAD) patients and 14 healthy controls on a corpus of 192 single words in which the following perceptual properties were manipulated systematically: inter-letter spacing, font size, length, font type, case and confusability. PCA reading was significantly less accurate and slower than tAD patients and controls, with performance significantly adversely affected by increased letter spacing, size, length and font (cursive < non-cursive), and characterised by visual errors (69% of all error responses). By contrast, tAD and control accuracy rates were at or near ceiling, letter spacing was the only perceptual factor to influence reading speed in the same direction as controls, and, in contrast to PCA patients, control reading was faster for larger font sizes. The inverse size effect in PCA (less accurate reading of large than small font size print) was associated with lower grey matter volume in the right superior parietal lobule. Reading accuracy was associated with impairments of early visual (especially crowding), visuoperceptual and visuospatial processes. However, these deficits were not causally related to a universal impairment of reading as some patients showed preserved reading for small, unspaced words despite grave visual deficits. Rather, the impact of specific types of visual dysfunction on reading was found to be (con)text specific, being particularly evident for large, spaced, lengthy words. These findings improve the characterisation of dyslexia in PCA, shed light on the causative and associative factors, and provide clear direction for the development of reading aids and strategies to maximise and sustain reading ability in the early stages of disease.
doi:10.1016/j.cortex.2014.03.010
PMCID: PMC4194349  PMID: 24841985
Posterior cortical atrophy (PCA); Alzheimer's disease (AD); Acquired dyslexia; Crowding
9.  Music, reward and frontotemporal dementia 
Brain  2014;137(10):e300.
doi:10.1093/brain/awu145
PMCID: PMC4163029  PMID: 24919970
10.  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
11.  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
12.  A Novel Prion Disease Associated with Diarrhea and Autonomic Neuropathy 
The New England journal of medicine  2013;369(20):10.1056/NEJMoa1214747.
BACKGROUND
Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multi-focal central nervous system degeneration that is usually dominated by dementia and cerebellar ataxia. Approximately 15% of cases of recognized prion disease are inherited and associated with coding mutations in the gene encoding prion protein (PRNP). The availability of genetic diagnosis has led to a progressive broadening of the recognized spectrum of disease.
METHODS
We used longitudinal clinical assessments over a period of 20 years at one hospital combined with genealogical, neuropsychological, neurophysiological, neuroimaging, pathological, molecular genetic, and biochemical studies, as well as studies of animal transmission, to characterize a novel prion disease in a large British kindred. We studied 6 of 11 affected family members in detail, along with autopsy or biopsy samples obtained from 5 family members.
RESULTS
We identified a PRNP Y163X truncation mutation and describe a distinct and consistent phenotype of chronic diarrhea with autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy with an onset in early adulthood. Cognitive decline and seizures occurred when the patients were in their 40s or 50s. The deposition of prion protein amyloid was seen throughout peripheral organs, including the bowel and peripheral nerves. Neuropathological examination during end-stage disease showed the deposition of prion protein in the form of frequent cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy. A unique pattern of abnormal prion protein fragments was seen in brain tissue. Transmission studies in laboratory mice were negative.
CONCLUSIONS
Abnormal forms of prion protein that were found in multiple peripheral tissues were associated with diarrhea, autonomic failure, and neuropathy. (Funded by the U.K. Medical Research Council and others.)
doi:10.1056/NEJMoa1214747
PMCID: PMC3863770  PMID: 24224623
13.  Impairments of auditory scene analysis in Alzheimer's disease 
Brain  2011;135(1):190-200.
Parsing of sound sources in the auditory environment or ‘auditory scene analysis’ is a computationally demanding cognitive operation that is likely to be vulnerable to the neurodegenerative process in Alzheimer’s disease. However, little information is available concerning auditory scene analysis in Alzheimer's disease. Here we undertook a detailed neuropsychological and neuroanatomical characterization of auditory scene analysis in a cohort of 21 patients with clinically typical Alzheimer's disease versus age-matched healthy control subjects. We designed a novel auditory dual stream paradigm based on synthetic sound sequences to assess two key generic operations in auditory scene analysis (object segregation and grouping) in relation to simpler auditory perceptual, task and general neuropsychological factors. In order to assess neuroanatomical associations of performance on auditory scene analysis tasks, structural brain magnetic resonance imaging data from the patient cohort were analysed using voxel-based morphometry. Compared with healthy controls, patients with Alzheimer's disease had impairments of auditory scene analysis, and segregation and grouping operations were comparably affected. Auditory scene analysis impairments in Alzheimer's disease were not wholly attributable to simple auditory perceptual or task factors; however, the between-group difference relative to healthy controls was attenuated after accounting for non-verbal (visuospatial) working memory capacity. These findings demonstrate that clinically typical Alzheimer's disease is associated with a generic deficit of auditory scene analysis. Neuroanatomical associations of auditory scene analysis performance were identified in posterior cortical areas including the posterior superior temporal lobes and posterior cingulate. This work suggests a basis for understanding a class of clinical symptoms in Alzheimer's disease and for delineating cognitive mechanisms that mediate auditory scene analysis both in health and in neurodegenerative disease.
doi:10.1093/brain/awr260
PMCID: PMC3267978  PMID: 22036957
Alzheimer's disease; auditory scene analysis; auditory processing; voxel-based morphometry
14.  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
15.  Auditory tracts identified with combined fMRI and diffusion tractography 
Neuroimage  2014;84(100):562-574.
The auditory tracts in the human brain connect the inferior colliculus (IC) and medial geniculate body (MGB) to various components of the auditory cortex (AC). While in non-human primates and in humans, the auditory system is differentiated in core, belt and parabelt areas, the correspondence between these areas and anatomical landmarks on the human superior temporal gyri is not straightforward, and at present not completely understood. However it is not controversial that there is a hierarchical organization of auditory stimuli processing in the auditory system. The aims of this study were to demonstrate that it is possible to non-invasively and robustly identify auditory projections between the auditory thalamus/brainstem and different functional levels of auditory analysis in the cortex of human subjects in vivo combining functional magnetic resonance imaging (fMRI) with diffusion MRI, and to investigate the possibility of differentiating between different components of the auditory pathways (e.g. projections to areas responsible for sound, pitch and melody processing). We hypothesized that the major limitation in the identification of the auditory pathways is the known problem of crossing fibres and addressed this issue acquiring DTI with b-values higher than commonly used and adopting a multi-fibre ball-and-stick analysis model combined with probabilistic tractography. Fourteen healthy subjects were studied. Auditory areas were localized functionally using an established hierarchical pitch processing fMRI paradigm. Together fMRI and diffusion MRI allowed the successful identification of tracts connecting IC with AC in 64 to 86% of hemispheres and left sound areas with homologous areas in the right hemisphere in 86% of hemispheres. The identified tracts corresponded closely with a three-dimensional stereotaxic atlas based on postmortem data. The findings have both neuroscientific and clinical implications for delineation of the human auditory system in vivo.
Highlights
•We combine fMRI and DTI to successfully identify the auditory pathways in volunteers.•Tractography results are comparable to postmortem atlas data.•Clinical fMRI/DTI can successfully identify cortico-subcortical auditory pathways.•Ascending and descending auditory pathways cannot be differentiated with MRI.
doi:10.1016/j.neuroimage.2013.09.007
PMCID: PMC3898984  PMID: 24051357
AC, auditory cortex; AM, amplitude modulation; BOLD, blood oxygenation level dependent; CoG, centre of gravity; cSD, constrained spherical deconvolution; DSI, diffusion spectrum imaging; DTI, diffusion tensor imaging; EPI, echo planar imaging; FDR, false discovery rate; fMRI, functional magnetic resonance imaging; HG, Heschl's gyrus; IndConn, index of connectivity; IC, inferior colliculus; IRN, iterated ripple noise; MGB, medial geniculate body; MNI, Montreal Neurological Institute; MRI, magnetic resonance imaging; PAS, persistent angular structure; PET, positron emission tomography; PP, planum polaris; PT, planum temporalis; SD, spherical deconvolution; SN, substantia nigra; STG, superior temporal gyrus; Auditory tracts; Auditory radiation; fMRI; DTI; Tractography
16.  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
17.  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
18.  Intact reading in patients with profound early visual dysfunction 
Despite substantial neuroscientific evidence for a region of visual cortex dedicated to the processing of written words, many studies continue to reject explanations of letter-by-letter (LBL) reading in terms of impaired word form representations or parallel letter processing in favour of more general deficits of visual function. In the current paper, we demonstrate that whilst LBL reading is often associated with general visual deficits, these deficits are not necessarily sufficient to cause reading impairment and have led to accounts of LBL reading which are based largely on evidence of association rather than causation. We describe two patients with posterior cortical atrophy (PCA) who exhibit remarkably preserved whole word and letter reading despite profound visual dysfunction. Relative to controls, both patients demonstrated impaired performance on tests of early visual, visuoperceptual and visuospatial processing; visual acuity was the only skill preserved in both individuals. By contrast, both patients were able to read aloud words with perfect to near-perfect accuracy. Reading performance was also rapid with no overall significant difference in response latencies relative to age- and education-matched controls. Furthermore, the patients violated a key prediction of general visual accounts of LBL reading – that pre-lexical impairments should result in prominent word length effects; in the two reported patients, evidence for abnormal word length effects was equivocal or absent, and certainly an order of magnitude different to that reported for LBL readers. We argue that general visual accounts cannot explain the pattern of reading data reported, and attribute the preserved reading performance to preserved direct access to intact word form representations and/or parallel letter processing mechanisms. The current data emphasise the need for much clearer evidence of causality when attempting to draw connections between specific aspects of visual processing and different types of acquired peripheral dyslexia.
doi:10.1016/j.cortex.2013.01.009
PMCID: PMC3902200  PMID: 23578749
Posterior cortical atrophy (PCA); Alzheimer's disease (AD); Letter-by-letter reading; Pure alexia; Word form dyslexia
19.  Agnosia for accents in primary progressive aphasia☆ 
Neuropsychologia  2013;51(9):1709-1715.
As an example of complex auditory signal processing, the analysis of accented speech is potentially vulnerable in the progressive aphasias. However, the brain basis of accent processing and the effects of neurodegenerative disease on this processing are not well understood. Here we undertook a detailed neuropsychological study of a patient, AA with progressive nonfluent aphasia, in whom agnosia for accents was a prominent clinical feature. We designed a battery to assess AA's ability to process accents in relation to other complex auditory signals. AA's performance was compared with a cohort of 12 healthy age and gender matched control participants and with a second patient, PA, who had semantic dementia with phonagnosia and prosopagnosia but no reported difficulties with accent processing. Relative to healthy controls, the patients showed distinct profiles of accent agnosia. AA showed markedly impaired ability to distinguish change in an individual's accent despite being able to discriminate phonemes and voices (apperceptive accent agnosia); and in addition, a severe deficit of accent identification. In contrast, PA was able to perceive changes in accents, phonemes and voices normally, but showed a relatively mild deficit of accent identification (associative accent agnosia). Both patients showed deficits of voice and environmental sound identification, however PA showed an additional deficit of face identification whereas AA was able to identify (though not name) faces normally. These profiles suggest that AA has conjoint (or interacting) deficits involving both apperceptive and semantic processing of accents, while PA has a primary semantic (associative) deficit affecting accents along with other kinds of auditory objects and extending beyond the auditory modality. Brain MRI revealed left peri-Sylvian atrophy in case AA and relatively focal asymmetric (predominantly right sided) temporal lobe atrophy in case PA. These cases provide further evidence for the fractionation of brain mechanisms for complex sound analysis, and for the stratification of progressive aphasia syndromes according to the signature of nonverbal auditory deficits they produce.
Highlights
•Deficits of accent processing can be a presenting feature of primary progressive aphasia.•Accent agnosia can dissociate from a generalised auditory agnosia.•Progressive aphasia syndromes show different profiles of accent processing deficits.
doi:10.1016/j.neuropsychologia.2013.05.013
PMCID: PMC3724054  PMID: 23721780
Primary progressive aphasia; Dementia; Accent processing; Phonagnosia; Prosopagnosia
20.  Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia 
Acta Neuropathologica  2013;126(3):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
21.  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
22.  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
23.  A Hypnic Hypothesis of Alzheimer's Disease 
Neuro-Degenerative Diseases  2013;12(4):165-176.
Background
Understanding the pathophysiology of Alzheimer's disease (AD) is of fundamental importance for improved diagnosis, monitoring and ultimately, treatment.
Objective
A role for the sleep-wake cycle in the pathogenesis of AD has been proposed, but remains to be worked out in detail.
Methods
Here we draw together several lines of previous work to outline a ‘hypnic hypothesis’ of AD.
Results
We propose that altered function of brainstem neurotransmitter pathways associated with sleep, promotes regionally specific disintegration of a cortico-subcortical ‘default mode’ brain network that is selectively vulnerable in AD.
Conclusion
The formation of a dynamic toxic state within this vulnerable network linked to sleep-wake disruption, would in turn lead to failure of synaptic repair, increased transmission of pathogenic misfolded proteins and a self-amplifying neurodegenerative process. We consider the evidence for this hypnic hypothesis and the implications that follow on from it.
doi:10.1159/000350060
PMCID: PMC3884167  PMID: 23635607
Sleep; Alzheimer's disease; Neurodegeneration; Default mode network

24.  Early-onset Alzheimer disease clinical variants 
Neurology  2012;79(1):80-84.
Objective:
To assess patterns of reduced cortical thickness in different clinically defined variants of early-onset Alzheimer disease (AD) and to explore the hypothesis that these variants span a phenotypic continuum rather than represent distinct subtypes.
Methods:
The case-control study included 25 patients with posterior cortical atrophy (PCA), 15 patients with logopenic progressive aphasia (LPA), and 14 patients with early-onset typical amnestic AD (tAD), as well as 30 healthy control subjects. Cortical thickness was measured using FreeSurfer, and differences and commonalities in patterns of reduced cortical thickness were assessed between patient groups and controls. Given the difficulty of using mass-univariate statistics to test ideas of continuous variation, we use multivariate machine learning algorithms to visualize the spectrum of subjects and to assess separation of patient groups from control subjects and from each other.
Results:
Although each patient group showed disease-specific reductions in cortical thickness compared with control subjects, common areas of cortical thinning were identified, mainly involving temporoparietal regions. Multivariate analyses permitted clear separation between control subjects and patients and moderate separation between patients with PCA and LPA, while patients with tAD were distributed along a continuum between these extremes. Significant classification performance could nevertheless be obtained when every pair of patient groups was compared directly.
Conclusions:
Analyses of cortical thickness patterns support the hypothesis that different clinical presentations of AD represent points in a phenotypic spectrum of neuroanatomical variation. Machine learning shows promise for syndrome separation and for identifying common anatomic patterns across syndromes that may signify a common pathology, both aspects of interest for treatment trials. Neurology® 2012;79:80–84
doi:10.1212/WNL.0b013e31825dce28
PMCID: PMC3385494  PMID: 22722624
25.  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

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