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Authors: Hailstone, Julia C. | Crutch, Sebastian J. | Warren, Jason D.

Article Type: Research Article

DOI: 10.3233/BEN-2010-0284

Citation: Behavioural Neurology, vol. 23, no. 4, pp. 163-164, 2010

Authors: Mahoney, Colin J. | Downey, Laura E. | Beck, Jon | Liang, Yuying | Mead, Simon | Perry, Richard J. | Warren, Jason D.

Article Type: Short Communication

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.

Keywords: Familial Alzheimer's disease, Presenilin 1, primary progressive aphasia

DOI: 10.3233/JAD-122092

Citation: Journal of Alzheimer's Disease, vol. 36, no. 2, pp. 239-243, 2013

Authors: Rohrer, Jonathan D. | Clarkson, Matthew J. | Kittus, Raivo | Rossor, Martin N. | Ourselin, Sebastien | Warren, Jason D. | Fox, Nick C.

Article Type: Research Article

Abstract: Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder which presents with either behavioral or language impairment. The two language syndromes are known as progressive nonfluent aphasia (PNFA) and semantic dementia (SEMD). While cross-sectional imaging patterns of brain atrophy are well-described in FTLD, fewer studies have investigated longitudinal imaging changes. We measured longitudinal hemispheric and lobar atrophy rates using serial MRI in a cohort of 18 patients with PNFA and 17 patients with SEMD as well as 14 cognitively-normal control subjects. We subsequently calculated sample size estimates for clinical trials. Rates of left hemisphere atrophy were greater than rates of right …hemisphere atrophy in both PNFA and SEMD with no significant differences between the groups. The disease groups showed asymmetrical atrophy (more severe on the left) at baseline with significantly increasing asymmetry over time. Within a hemisphere, the fastest rate of atrophy varied between lobes: in SEMD temporal > frontal > parietal > occipital, while in PNFA frontal > temporal/parietal > occipital. In SEMD, using temporal lobe measures of atrophy in clinical trials would provide the lowest sample sizes necessary, while in PNFA left hemisphere atrophy measures provided the lowest sample size. These patterns provide information about disease evolution in the FTLD language variants that is of both clinical and neurobiological relevance. Show more

Keywords: Frontotemporal dementia, primary progressive aphasia

DOI: 10.3233/JAD-2012-111556

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 407-411, 2012

Authors: Bocchetta, Martina | Iglesias, Juan Eugenio | Scelsi, Marzia A. | Cash, David M. | Cardoso, M. Jorge | Modat, Marc | Altmann, Andre | Ourselin, Sebastien | Warren, Jason D. | Rohrer, Jonathan D.

Article Type: Research Article

Abstract: Background: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder, with a strong genetic component. Previous research has shown that medial temporal lobe atrophy is a common feature of FTD. However, no study has so far investigated the differential vulnerability of the hippocampal subfields in FTD. Objectives: We aimed to investigate hippocampal subfield volumes in genetic FTD. Methods: We in6/2/2018vestigated hippocampal subfield volumes in a cohort of 75 patients with genetic FTD (age: mean (standard deviation) 59.3 (7.7) years; disease duration: 5.1 (3.4) years; 29 with MAPT , 28 with C9orf72 , and 18 with GRN mutations) compared with 97 age-matched …controls (age: 62.1 (11.1) years). We performed a segmentation of their volumetric T1-weighted MRI scans to extract hippocampal subfields volumes. Left and right volumes were summed and corrected for total intracranial volumes. Results: All three groups had smaller hippocampi than controls. The MAPT group had the most atrophic hippocampi, with the subfields showing the largest difference from controls being CA1-4 (24–27%, p < 0.0005). For C9orf72 , the CA4, CA1, and dentate gyrus regions (8–11%, p < 0.0005), and for GRN the presubiculum and subiculum (10–14%, p < 0.0005) showed the largest differences from controls. Conclusions: The hippocampus was affected in all mutation types but a different pattern of subfield involvement was found in the three genetic groups, consistent with differential cortical-subcortical network vulnerability. Show more

Keywords: Genetic frontotemporal dementia, hippocampal subfields, magnetic resonance imaging, volumetry

DOI: 10.3233/JAD-180195

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 497-504, 2018

Authors: Lehmann, Manja | Rohrer, Jonathan D. | Clarkson, Matthew J. | Ridgway, Gerard R. | Scahill, Rachael I. | Modat, Marc | Warren, Jason D. | Ourselin, Sebastien | Barnes, Josephine | Rossor, Martin N. | Fox, Nick C.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) can be difficult to differentiate clinically due to overlapping symptoms. Subject classification in research studies is often based on clinical rather than pathological criteria which may mean some subjects are misdiagnosed and misclassified. Recently, methods measuring cortical thickness using magnetic resonance imaging have been suggested to be effective in differentiating between clinically-defined AD and frontotemporal dementia (FTD) in addition to showing disease-related patterns of atrophy. In this study we used FreeSurfer, a freely-available and automated software tool, to measure cortical thickness in 28 pathologically-confirmed AD patients, of which 11 had a typical …amnestic presentation and 17 an atypical presentation during life, 23 pathologically-confirmed FTLD subjects, and 25 healthy controls. Patients with AD pathology, irrespective of clinical diagnosis, showed reduced cortical thickness bilaterally in the medial temporal lobe, posterior cingulate gyrus, precuneus, posterior parietal lobe, and frontal pole compared with controls. We further showed that lower cortical thickness in the posterior cingulate gyrus, parietal lobe, and frontal pole is suggestive of AD pathology in patients with behavioral or language deficits. In contrast, lower cortical thickness in the anterior temporal lobe and frontal lobe is indicative of the presence of FTLD pathology in patients with a clinical presentation of FTD. Reduced cortical thickness in the posterior cingulate gyrus is characteristic of AD pathology in patients with typical and atypical clinical presentations of AD, and may assist a clinical distinction of AD pathology from FTLD pathology. Show more

Keywords: Alzheimer's disease, cortical thickness, FreeSurfer, magnetic resonance imaging, pathology

DOI: 10.3233/JAD-2010-1401

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 587-598, 2010

Authors: Scahill, Rachael I. | Ridgway, Gerard R. | Bartlett, Jonathan W. | Barnes, Josephine | Ryan, Natalie S. | Mead, Simon | Beck, Jonathan | Clarkson, Matthew J. | Crutch, Sebastian J. | Schott, Jonathan M. | Ourselin, Sebastien | Warren, Jason D. | Hardy, John | Rossor, Martin N. | Fox, Nick C.

Article Type: Research Article

Abstract: Mutations in the presenilin1 (PSEN1) and amyloid β-protein precursor (APP) genes account for the majority of cases of autosomal dominantly inherited Alzheimer's disease (AD). We wished to assess and compare the patterns of cerebral loss produced by these two groups of mutations. Volumetric magnetic resonance imaging and neuropsychological assessments were performed in individuals with clinical AD carrying mutations in the APP (n = 10) and PSEN1 (n = 18) genes and in healthy controls (n = 18). Voxel-based morphometry (VBM), cortical thickness, and region of interest analyses were performed. Mini-Mental State Examination scores were similar in the two disease groups …suggesting similar levels of disease severity. There was evidence that APP subjects have smaller hippocampal volume compared with PSEN1 subjects (p = 0.007), and weak evidence that they have larger whole-brain and grey matter volumes (both p = 0.07). Although there was no evidence of statistically significant differences between APP and PSEN1 in VBM or cortical thickness analyses, effect-maps were suggestive of APP subjects having more medial temporal lobe atrophy and conversely PSEN1 subjects showing more neocortical loss. Neuropsychological data were consistent with these regional differences and suggested greater memory deficits in the APP patients and greater impairment in non-memory domains in the PSEN1 group, although these differences were not statistically significant. We conclude that the mechanisms by which APP and PSEN1 mutations cause neuronal loss may differ which furthers our understanding of the neuropathology underlying AD and may inform future therapeutic strategies and trial designs. Show more

Keywords: Alzheimer's disease, APP, atrophy, autosomal dominant, magnetic resonance imaging, PSEN1

DOI: 10.3233/JAD-121255

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 199-212, 2013

Authors: Weston, Philip S.J. | Paterson, Ross W. | Dickson, John | Barnes, Anna | Bomanji, Jamshed B. | Kayani, Irfan | Lunn, Michael P. | Mummery, Catherine J. | Warren, Jason D. | Rossor, Martin N. | Fox, Nick C. | Zetterberg, Henrik | Schott, Jonathan M.

Article Type: Short Communication

Abstract: Cerebrospinal fluid (CSF) measures of amyloid and tau are the first-line Alzheimer’s disease biomarkers in many clinical centers. We assessed if and when the addition of amyloid PET following CSF measurements provides added diagnostic value. Twenty patients from a cognitive clinic, who had undergone detailed assessment including CSF measures, went on to have amyloid PET. The treating neurologist’s working diagnosis, and degree of diagnostic certainty, was assessed both before and after the PET. Amyloid PET changed the diagnosis in 7/20 cases. Amyloid PET can provide added diagnostic value, particularly in young-onset, atypical dementias, where CSF results are borderline and diagnostic …uncertainty remains. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, clinical decision-making, diagnosis, PET

DOI: 10.3233/JAD-160302

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1297-1302, 2016

Authors: Clark, Camilla N. | Nicholas, Jennifer M. | Gordon, Elizabeth | Golden, Hannah L. | Cohen, Miriam H. | Woodward, Felix J. | Macpherson, Kirsty | Slattery, Catherine F. | Mummery, Catherine J. | Schott, Jonathan M. | Rohrer, Jonathan D. | Warren, Jason D.

Article Type: Research Article

Abstract: Sense of humor is potentially relevant to social functioning in dementias, but has been little studied in these diseases. We designed a semi-structured informant questionnaire to assess humor behavior and preferences in patients with behavioral variant frontotemporal dementia (bvFTD; n  = 15), semantic dementia (SD; n  = 7), progressive nonfluent aphasia (PNFA; n  = 10), and Alzheimer’s disease (AD; n  = 16) versus healthy age-matched individuals (n  = 21). Altered (including frankly inappropriate) humor responses were significantly more frequent in bvFTD and SD (all patients) than PNFA or AD (around 40% of patients). All patient groups liked satirical and absurdist comedy significantly less than did …healthy controls. This pattern was reported premorbidly for satirical comedy in bvFTD, PNFA, and AD. Liking for slapstick comedy did not differ between groups. Altered sense of humor is particularly salient in bvFTD and SD, but also frequent in AD and PNFA. Humor may be a sensitive probe of social cognitive impairment in dementia, with diagnostic, biomarker and social implications. Show more

Keywords: Alzheimer’s disease, comedy, dementia, frontotemporal dementia, humor, progressive aphasia, semantic dementia

DOI: 10.3233/JAD-150413

Citation: Journal of Alzheimer's Disease, vol. 49, no. 1, pp. 111-119, 2016

Authors: Hardy, Chris J.D. | Buckley, Aisling H. | Downey, Laura E. | Lehmann, Manja | Zimmerer, Vitor C. | Varley, Rosemary A. | Crutch, Sebastian J. | Rohrer, Jonathan D. | Warrington, Elizabeth K. | Warren, Jason D.

Article Type: Research Article

Abstract: Background: The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined. Objective: We aimed to quantify the extent of language deficits in this patient group. Methods: We assessed a cohort of patients with bvFTD (n  = 24) in relation to patients with semantic variant primary progressive aphasia (svPPA; n  = 14), nonfluent variant primary progressive aphasia (nfvPPA; n  = 18), and healthy age-matched individuals (n  = 24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients’ brain magnetic resonance images. Results: Relative to healthy …controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech, and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network. Conclusions: bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker. Show more

Keywords: Behavioral variant frontotemporal dementia, frontotemporal dementia, primary progressive aphasia

DOI: 10.3233/JAD-150806

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 359-371, 2016

Authors: Golden, Hannah L. | Clark, Camilla N. | Nicholas, Jennifer M. | Cohen, Miriam H. | Slattery, Catherine F. | Paterson, Ross W. | Foulkes, Alexander J.M. | Schott, Jonathan M. | Mummery, Catherine J. | Crutch, Sebastian J. | Warren, Jason D.

Article Type: Research Article

Abstract: Despite much recent interest in music and dementia, music perception has not been widely studied across dementia syndromes using an information processing approach. Here we addressed this issue in a cohort of 30 patients representing major dementia syndromes of typical Alzheimer’s disease (AD, n  = 16), logopenic aphasia (LPA, an Alzheimer variant syndrome; n  = 5), and progressive nonfluent aphasia (PNFA; n  = 9) in relation to 19 healthy age-matched individuals. We designed a novel neuropsychological battery to assess perception of musical patterns in the dimensions of pitch and temporal information (requiring detection of notes that deviated from the established pattern based on …local or global sequence features) and musical scene analysis (requiring detection of a familiar tune within polyphonic harmony). Performance on these tests was referenced to generic auditory (timbral) deviance detection and recognition of familiar tunes and adjusted for general auditory working memory performance. Relative to healthy controls, patients with AD and LPA had group-level deficits of global pitch (melody contour) processing while patients with PNFA as a group had deficits of local (interval) as well as global pitch processing. There was substantial individual variation within syndromic groups. Taking working memory performance into account, no specific deficits of musical temporal processing, timbre processing, musical scene analysis, or tune recognition were identified. The findings suggest that particular aspects of music perception such as pitch pattern analysis may open a window on the processing of information streams in major dementia syndromes. The potential selectivity of musical deficits for particular dementia syndromes and particular dimensions of processing warrants further systematic investigation. Show more

Keywords: Alzheimer’s disease, auditory scene analysis, dementia, logopenic aphasia, music, progressive nonfluent aphasia

DOI: 10.3233/JAD-160359

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 933-949, 2017