Jason D Warren

University College London, Londinium, England, United Kingdom

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Publications (135)830.45 Total impact

  • Brain : a journal of neurology. 06/2014;
  • Camilla N Clark, Laura E Downey, Jason D Warren
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    ABSTRACT: Despite its evident universality and high social value, the ultimate biological role of music and its connection to brain disorders remain poorly understood. Recent findings from basic neuroscience have shed fresh light on these old problems and new insights provided by clinical neuroscience concerning the effects of brain disorders promise to be particularly valuable in uncovering the underlying cognitive and neural architecture of music and for assessing candidate accounts of the biological role of music. Here we advance a new model of the biological role of music in human evolution and the link to brain disorders, drawing on diverse lines of evidence derived from comparative ethology, cognitive neuropsychology and neuroimaging studies in the normal and disordered brain. We propose that music evolved from the call signals of our hominid ancestors as a means mentally to rehearse and predict potentially costly, affectively-laden social routines in surrogate, coded, low-cost form: essentially, a mechanism for transforming emotional mental states efficiently and adaptively into social signals. This biological role of music has its legacy today in the disordered processing of music and mental states that characterises certain developmental and acquired clinical syndromes of brain network disintegration.
    Social Cognitive and Affective Neuroscience 05/2014; · 5.04 Impact Factor
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    ABSTRACT: Semantic dementia is a unique clinicopathological syndrome in the frontotemporal lobar degeneration spectrum. It is characterized by progressive and relatively selective impairment of semantic memory, associated with asymmetric antero-inferior temporal lobe atrophy. Although the syndrome became widely recognized only in the 1980s, descriptions of cases with typical features of semantic dementia have been on record for over a century. Here, we draw attention to a well documented historical case of a patient with features that would have fulfilled current consensus criteria for semantic dementia, as reconstructed from the notes made by her neurologist, Macdonald Critchley, in 1938. This case raises a number of issues concerning the nosology of the semantic dementia syndrome and the potential value of archived case material.
    Neurocase 05/2014; · 1.05 Impact Factor
  • Camilla N Clark, Laura E Downey, Jason D Warren
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    ABSTRACT: Some healthy people fail to derive pleasure from music despite otherwise preserved perceptual and reward responses. Such 'musical anhedonia' implies the existence of music-specific brain reward mechanisms, which could provide a substrate for music to acquire biological value.
    Current biology: CB 03/2014; 24(6):R234-7. · 10.99 Impact Factor
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    ABSTRACT: Mutations in C9ORF72 are an important cause of frontotemporal dementia (FTD) and motor neuron disease. Accumulating evidence suggests that FTD associated with C9ORF72 mutations (C9ORF72-FTD) is distinguished clinically by early prominent neuropsychiatric features that might collectively reflect deranged body schema processing. However, the pathophysiology of C9ORF72-FTD has not been elucidated. We undertook a detailed neurophysiological investigation of five patients with C9ORF72-FTD, in relation to patients with FTD occurring sporadically and on the basis of mutations in the microtubule-associated protein tau gene and healthy older individuals. We designed or adapted behavioural tasks systematically to assess aspects of somatosensory body schema processing (tactile discrimination, proprioceptive and body part illusions and self/non-self differentiation). Patients with C9ORF72-FTD selectively exhibited deficits at these levels of body schema processing in relation to healthy individuals and other patients with FTD. Altered body schema processing is a novel, generic pathophysiological mechanism that may link the distributed cortico-subcortical network previously implicated in C9ORF72-FTD with a wide range of neuropsychiatric and behavioural symptoms, and constitute a physiological marker of this neurodegenerative proteinopathy.
    Journal of neurology, neurosurgery, and psychiatry 02/2014; · 4.87 Impact Factor
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    ABSTRACT: Despite considerable interest in improving clinical and neurobiological characterisation of frontotemporal dementia and in defining the role of brain network disintegration in its pathogenesis, information about white matter pathway alterations in frontotemporal dementia remains limited. Here we investigated white matter tract damage using an unbiased, template-based diffusion tensor imaging (DTI) protocol in a cohort of 27 patients with the behavioral variant of frontotemporal dementia (bvFTD) representing both major genetic and sporadic forms, in relation both to healthy individuals and to patients with Alzheimer's disease. Widespread white matter tract pathology was identified in the bvFTD group compared with both healthy controls and Alzheimer's disease group, with prominent involvement of uncinate fasciculus, cingulum bundle and corpus callosum. Relatively discrete and distinctive white matter profiles were associated with genetic subgroups of bvFTD associated with MAPT and C9ORF72 mutations. Comparing diffusivity metrics, optimal overall separation of the bvFTD group from the healthy control group was signalled using radial diffusivity, whereas optimal overall separation of the bvFTD group from the Alzheimer's disease group was signalled using fractional anisotropy. Comparing white matter changes with regional grey matter atrophy (delineated using voxel based morphometry) in the bvFTD cohort revealed co-localisation between modalities particularly in the anterior temporal lobe, however white matter changes extended widely beyond the zones of grey matter atrophy. Our findings demonstrate a distributed signature of white matter alterations that is likely to be core to the pathophysiology of bvFTD and further suggest that this signature is modulated by underlying molecular pathologies. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    Human Brain Mapping 02/2014; · 6.88 Impact Factor
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    ABSTRACT: 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 patients (tAD) 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.
    Cortex 01/2014; · 6.16 Impact Factor
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    ABSTRACT: Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multifocal 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. 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. 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. 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.).
    New England Journal of Medicine 11/2013; 369(20):1904-14. · 51.66 Impact Factor
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    ABSTRACT: Identification of a specific genetic cause of early onset dementia (EOD) is important but can be difficult because of pleiotropy, locus heterogeneity and accessibility of gene tests. Here we assess the use of next generation sequencing (NGS) technologies as a quick, accurate and cost effective method to determine genetic diagnosis in EOD. We developed gene panel based technologies to assess 16 genes known to harbour mutations causal of dementia and combined these with PCR based assessments of the C9orf72 hexanucleotide repeat expansion and the octapeptide repeat region of PRNP. In a blinded study of 95 samples we show very high sensitivity and specificity are achievable using either Ion Torrent or MiSeq sequencing platforms. Modifications to the gene panel permit accurate detection of structural variation in APP. In 2/10 samples which had been selected because they possess a variant of uncertain significance the new technology discovered a causal mutation in genes not previously sequenced. A large proportion (23/85) of samples showed genetic variants of uncertain significance in addition to known mutations. The MRC Dementia Gene Panel and similar technologies are likely to be transformational in EOD diagnosis with a significant impact on the proportion of patients in whom a genetic cause is identified.
    Neurobiology of aging 08/2013; · 5.94 Impact Factor
  • Journal of neurology, neurosurgery, and psychiatry 07/2013; · 4.87 Impact Factor
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    ABSTRACT: 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 clinico-anatomical 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 neuro-cognitive basis of phobias more generally.
    Behavioural neurology 07/2013; · 1.25 Impact Factor
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    ABSTRACT: 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.
    Trends in Neurosciences 07/2013; · 13.58 Impact Factor
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    ABSTRACT: 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.
    Acta Neuropathologica 07/2013; · 9.73 Impact Factor
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    ABSTRACT: 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.
    Neuropsychologia 05/2013; · 3.48 Impact Factor
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    ABSTRACT: 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.
    JAMA neurology. 05/2013;
  • Camilla N Clark, Jason D Warren
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    ABSTRACT: 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.
    Neurodegenerative Diseases 04/2013; · 3.41 Impact Factor
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    ABSTRACT: 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.
    Journal of Alzheimer's disease: JAD 04/2013; · 4.17 Impact Factor
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    Journal of neurology, neurosurgery, and psychiatry 02/2013; · 4.87 Impact Factor
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    ABSTRACT: Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800-4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.
    The American Journal of Human Genetics 02/2013; · 11.20 Impact Factor

Publication Stats

3k Citations
830.45 Total Impact Points

Institutions

  • 2002–2014
    • University College London
      • • Centre for Obesity Research
      • • Department of Neurodegenerative Disease
      • • Institute of Neurology
      • • Institute of Cognitive Neuroscience
      Londinium, England, United Kingdom
  • 2005–2013
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2002–2009
    • Royal Adelaide Hospital
      • • Department of Neurology
      • • Department of Medicine
      Tarndarnya, South Australia, Australia
  • 2008
    • Goldsmiths, University of London
      • Department of Psychology
      London, ENG, United Kingdom
  • 2002–2007
    • Newcastle University
      • Institute of Neuroscience
      Newcastle upon Tyne, ENG, United Kingdom
  • 2006
    • Imperial College London
      Londinium, England, United Kingdom