Anna Richardson

The University of Manchester, Manchester, England, United Kingdom

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Publications (47)346.32 Total impact

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    J B Lilleker · E A Lim · M Jones · A M T Richardson
    Journal of neurology, neurosurgery, and psychiatry 07/2015; DOI:10.1136/jnnp-2015-310815 · 6.81 Impact Factor
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    ABSTRACT: We previously reported1 that expansions in the C9orf72 gene, identified by Southern blotting or using a repeat primed PCR assay,2 may go undetected using an alternative, standard PCR assay.3 We attributed this discrepancy to a 10 base pair deletion adjacent to the expansion which was presumed to interfere with genotyping.1 To determine the possible clinical and pathological relevance of the deletion, we compared patients in whom the C9orf72 expansion was detected using the Renton3 assay (C9 reference group) with those carrying an expansion not detected by this method (deletion group).
    Journal of neurology, neurosurgery, and psychiatry 04/2015; DOI:10.1136/jnnp-2015-310441 · 6.81 Impact Factor
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    ABSTRACT: Cognitive impairment is common in patients with the neurodegenerative tauopathy progressive supranuclear palsy (PSP). Although a pattern of 'subcortical' cognitive impairment is considered prototypical in PSP, pathological and clinical observations suggest an overlap with frontotemporal dementia (FTD). Our objective was to evaluate behavioural and cognitive symptoms in a retrospective study of patients with PSP syndrome (PSPS) and their relationship to features seen in behavioural variant FTD. We reviewed the records of 62 patients (29 male, 33 female, median age 65.5 years) evaluated at a tertiary cognitive clinic who met NINDS-SPSP criteria for probable or possible PSP, and collected clinical details of their presenting history, cognitive and behavioural features. We also evaluated the proportion of patients fulfilling FTD Consensus criteria. Cognitive and behavioural symptoms were a predominant presenting feature in 58 % of patients evaluated. Cognitive slowing, executive impairments, and inefficient memory recall, consistent with 'subcortical' impairment, were identified in the majority of patients. Twenty patients (32 %) fulfilled cognitive and behavioural criteria for possible FTD at initial assessment, whereas behavioural changes not meeting formal diagnostic criteria were present in a greater proportion of the patients. Our findings support the existence of a spectrum of cognitive-behavioural features in PSPS, with significant clinical overlap with behavioural variant FTD. Cognitive and behavioural profiling should be an integral part of the assessment of patients with PSPS.
    Journal of Neurology 02/2015; 262(4). DOI:10.1007/s00415-015-7657-z · 3.38 Impact Factor
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    ABSTRACT: Pathological deposition of amyloid β (Aβ) protein is a key component in the pathogenesis of Alzheimer's disease (AD), but not a feature of frontotemporal dementia (FTD). PET ligands for Aβ protein are increasingly used in diagnosis and research of dementia syndromes. Here we report a PET study using (18)F-florbetapir in healthy control subjects and patients with AD and FTD. Ten healthy controls (mean age 62.5±5.2 years), 10 AD patients (mean age 62.6±4.5) and 8 FTD patients (mean age 62.5±9.6) were recruited to the study. All patients underwent detailed clinical and neuropsychological assessment, T1-weighted MR, and were genotyped for apolipoprotein E (APOE) status. All participants underwent dynamic (18)F-florbetapir PET on a high-resolution research tomograph, and FTD patients also underwent FDG PET scans. Standardised uptake value ratios (SUVRs) were extracted for predefined grey and white matter regions of interest using cerebellar grey matter as reference region. Static PET images were evaluated by trained raters blinded to clinical status and regional analysis. Total cortical grey matter florbetapir uptake values were significantly higher in AD (median SUVR 1.73) compared to FTD patients (1.13, P = 0.002) and controls (1.26, P = 0.04). Florbetapir uptake was also higher in AD compared to FTD and controls in frontal, parietal, occipital and cingulate cortex as well as central subcortical regions. Only one FTD patient (homozygous for APOE ϵ4) displayed high cortical florbetapir retention, while FDG PET demonstrated mesiofrontal hypometabolism consistent with the clinical diagnosis of FTD. The majority of visual raters classified 1 control (10%), 8 AD (80%), and 2 FTD (25%) patients as amyloid positive, while ratings were tied in another 2 FTD patients and 1 healthy control. Cortical (18)F-florbetapir uptake is low in the majority of FTD patients, providing good discrimination from AD. However, visual rating of FTD scans was challenging with a higher rate of discordance between readers than in AD and control subjects. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 02/2015; 56(3). DOI:10.2967/jnumed.114.147454 · 6.16 Impact Factor
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    ABSTRACT: Frontotemporal lobar degeneration is a highly familial disease and the most common known genetic cause is the repeat expansion mutation in the gene C9orf72. We have identified 2 brothers with an expansion mutation in C9orf72 using Southern blotting that is undetectable using repeat-primed polymerase chain reaction. Sequencing using high concentrations of DNA denaturants of a bacterial artificial chromosome clone obtained from one of the brothers identified a 10-base pair deletion adjacent to the expansion that presumably confers strong secondary structure that interferes with the genotyping. Using an alternative method, we have identified missed expansion carriers in our cohort, and this number has increased by approximately 25%. This observation has important implications for patients undergoing genetic testing for C9orf72. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 12/2014; 51(3). DOI:10.1016/j.neurobiolaging.2014.12.009 · 5.01 Impact Factor
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    ABSTRACT: Mutations in the gene p62/SQSTM1 have been reported as a relatively rare cause of frontotemporal lobar degeneration (FTLD). To establish whether this was the case for cases of FTLD from the United Kingdom, we sequenced the sequenced the entire open reading frame of this gene in a large cohort of patients. We identified 3 novel mutations in p62/SQSTM1 in 4 patients. One of these was a premature stop codon that removed the last 101 amino acids of the protein that presumably has a negative effect on protein function. Another mutation was also found in a case with a repeat expansion mutation in C9orf72 confirmed by Southern blot. These findings confirm a role of p62/SQSTM1 as a cause of FTLD. Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 10/2014; 36(3). DOI:10.1016/j.neurobiolaging.2014.08.035 · 5.01 Impact Factor
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    ABSTRACT: We have measured plasma progranulin and interleukin-6 in 230 patients with frontotemporal lobar degeneration (FTLD), 104 patients with Alzheimer's disease, and 161 control subjects. We have replicated previous findings of decreased levels of progranulin protein in FTLD because of mutations in GRN and show this is not observed in FTLD cases because of other causes. interleukin-6 levels were increased in FTLD overall, but these did not discriminate between clinical and genetic subtypes. Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 10/2014; 36(3). DOI:10.1016/j.neurobiolaging.2014.10.023 · 5.01 Impact Factor
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    ABSTRACT: Important insights into the pathogenic mechanism of Alzheimer's disease (AD) have arisen from the identification of genetic risk factors. Recently, a variant in the TREM2 gene (rs75932628), causing a C-to-T base-pair change that results in the substitution of histidine for arginine at amino acid position 47 (R47H) in the TREM2 protein, has been associated with an increased risk of AD. We, therefore, genotyped samples from a cohort of 474 AD patients and 608 healthy controls, from the northwest region of the UK, using allelic discrimination assays, to replicate the results of the previous studies. We show a significant association of the T allele of the rs75932628 variant of TREM2 with AD (allelic odds ratio 11.08, 95% confidence interval 2.55-48.09, and Yates' corrected p value = 0.000146). TREM2 is an innate immune receptor that regulates microglial cytokine production and phagocytosis, implying that dysregulation of these processes may be involved in AD pathology, with implications for disease management.
    Neurobiology of Aging 08/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.08.001 · 5.01 Impact Factor
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    ABSTRACT: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are considered to be part of a disease spectrum. However, with the exception of C9orf72, genes that cause ALS are rarely found to cause FTD and vice versa. To investigate this further, we have sequenced the ALS gene UBQLN2 in our FTD cohort and have found a single putative mutation. This further supports the concept that ALS genes are a rare cause of FTD.
    Neurobiology of Aging 08/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.08.002 · 5.01 Impact Factor
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    ABSTRACT: BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. METHODS: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms. FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. INTERPRETATION: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD
    The Lancet Neurology 07/2014; 3(7):686-99. DOI:10.1016/S1474-4422(14)70065-1 · 21.90 Impact Factor
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    ABSTRACT: Background Clinical criteria are important for improving diagnostic accuracy and ensuring comparability of patient cohorts in research studies. Objective The aim was to assess the National Institute on Aging and Alzheimer's Association (NIA-AA) criteria for Alzheimer's disease (AD) dementia in AD and frontotemporal lobar degeneration (FTLD). Methods Two hundred twelve consecutive patients with pathologically confirmed AD or FTLD who were clinically assessed in a specialist cognitive unit were identified. Fifty-five patients were excluded predominantly because of insufficient clinical information. Anonymized clinical data were rated against the NIA-AA criteria by raters who were blinded to clinical and pathologic diagnosis. Results The NIA-AA AD dementia criteria had a sensitivity of 65.6% for probable and 79.5% for possible AD and a specificity of 95.2% and 94.0% for probable and possible, respectively. Conclusion In patients with FTLD and predominantly early-onset AD, the NIA-AA AD dementia criteria have high specificity but lower sensitivity. The high specificity is due to the broad exclusion criteria.
    Alzheimer's and Dementia 07/2014; 11(2). DOI:10.1016/j.jalz.2014.04.516 · 12.41 Impact Factor
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    ABSTRACT: Background Delirium is common and is associated with an increased risk of dementia. However, it is not clear whether delirium confers increased risk of any particular type of dementia. We performed a retrospective study of Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB) to ascertain whether a suspected episode of preceding delirium was more common prior to diagnosis in either type of dementia. Methods The study was carried out in a tertiary referral unit for the diagnosis of dementia. Clinic letters from the first presentation to the unit of 85 cases with DLB and 95 cases of AD were reviewed for documentation of any previous episodes of suspected delirium. ResultsIn this study, 25% of DLB cases had at least one reported episode of suspected delirium as compared to 7% of AD cases (p=0.001). For the DLB cases who had a prior suspected delirium, 23% had more than one episode compared with 14% of the AD group. The median time between most recent suspected episode of delirium and diagnosis of dementia in both groups was less than a year ConclusionsA greater proportion of those presenting and diagnosed with DLB had a documentation of a suspected delirium than those diagnosed with AD. Delirium may lead to a higher risk of DLB as opposed to other forms of dementia, or delirium may, at least in some cases, represent the early stages of DLB. These data suggest that a diagnosis of DLB should be specifically considered in those presenting with a delirium. Copyright (c) 2013 John Wiley & Sons, Ltd.
    International Journal of Geriatric Psychiatry 02/2014; 29(2). DOI:10.1002/gps.3986 · 2.87 Impact Factor
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    ABSTRACT: We aimed to determine the extent to which patients with progressive language impairment conform to 2011 primary progressive aphasia (PPA) classification and to examine clinicopathologic correlations within PPA variants. Sixty-two consecutive patients with pathologically confirmed dementia who presented clinically with aphasia were identified. Patients with insufficient clinical information were excluded. PPA classifications were applied to anonymized clinical data taken from patients' initial assessment by raters who were blinded to clinical and pathologic diagnosis. The final cohort comprised 52 patients, 30 of whom met basic PPA criteria. Twenty-five patients met one of the 3 PPA classifications (13 logopenic, 8 nonfluent/agrammatic, and 4 semantic). Five patients did not meet the criteria for any of the PPA variants. All patients who met semantic variant PPA and 75% of patients who met nonfluent/agrammatic variant PPA classifications had frontotemporal lobar degeneration spectrum pathology. Pathologies were heterogeneous in patients who met logopenic variant PPA criteria (46% Alzheimer disease [AD], 8% AD mixed with dementia with Lewy bodies, 23% frontotemporal lobar degeneration, and 23% other). The 2011 PPA recommendations classify a large proportion of patients who meet basic PPA criteria. However, some patients had aphasic syndromes that could not be classified, suggesting that the 2011 recommendations do not cover the full range of PPA variants. Classification of semantic variant PPA provides a good prediction of underlying pathology. Classification of logopenic variant does not successfully differentiate PPA due to AD from PPA due to other pathologies.
    Neurology 10/2013; 81(21). DOI:10.1212/01.wnl.0000436070.28137.7b · 8.29 Impact Factor
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    ABSTRACT: Objective: We aimed to assess sensitivity and specificity of the updated criteria for behavioral variant frontotemporal dementia (bvFTD) based on a large autopsy-confirmed cohort of patients with dementia. Methods: Two hundred thirty-nine consecutive pathologically confirmed dementia patients, clinically assessed in a specialist cognitive unit were identified. Patients with predominant aphasia, motor disorders, or insufficient clinical information were excluded. Frontotemporal Dementia Consensus criteria were applied to anonymized clinical data taken from patients' initial assessment by raters who were blinded to clinical and pathologic diagnosis. Results: The final study cohort comprised 156 patients with predominantly early-onset dementia. The updated criteria for possible bvFTD had a sensitivity of 95% and specificity of 82%. Probable bvFTD criteria had a sensitivity of 85% and specificity of 95%. False positives were predominantly patients with presenile Alzheimer disease. Conclusion: Revised diagnostic criteria show encouragingly high sensitivity and specificity when applied to patients with early-onset dementia. They therefore provide a useful tool both for specialist researchers and general clinicians. There is a need for further prospective studies of sensitivity and specificity involving a broader spectrum of patients with dementia.
    Neurology 04/2013; 80(20). DOI:10.1212/WNL.0b013e318292a342 · 8.29 Impact Factor
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    ABSTRACT: Repeat expansions in C9orf72 are a major cause of frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Not all FTD-ALS patients show expansions. The study examined whether there are clinical differences between FTD-ALS patients with and without expansions in C9orf72. We examined case notes from consecutive FTD-ALS patients, screened for C9orf72 expansions, and documented demographic, neurological, behavioural and cognitive characteristics. Sixty patients met the selection criteria, of whom 11 showed expanded repeats (C9-positive) and 49 did not (C9-negative). A strong male bias was present in the C9-negative group only. A family history of FTD or ALS was recorded in both groups, but was significantly more common in C9-positive cases. Psychotic and irrational behaviours, apathy, disinhibition and loss of empathy were significantly more common in C9-positive cases, with a trend towards more frequent bulbar signs. No differences were found in onset age, presentation (ALS or FTD first), or cognitive changes (language and executive impairments). In conclusion, FTD-ALS is not clinically uniform. Phenotypic differences exist between patients with and without C9orf72 expansions, suggesting that FTD-ALS may be underpinned by distinct neurobiological substrates. The presence of psychiatric symptoms in the context of FTD-ALS should alert clinicians to the possibility of C9orf72 expansions.
    02/2013; 14(3). DOI:10.3109/21678421.2013.765485
  • Journal of neurology, neurosurgery, and psychiatry 07/2012; 83(10):1031-2. DOI:10.1136/jnnp-2012-303032 · 6.81 Impact Factor
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    ABSTRACT: Progressive non-fluent aphasia (PNFA) is typically associated with pathological changes consistent with frontotemporal lobar degeneration. A 65-year-old male presented with effortful speech, markedly impaired naming and features of speech apraxia, consistent with PNFA. Perceptuospatial function, calculation and executive function were intact. Brain SPECT showed left perisylvian hypoperfusion. He deteriorated profoundly over the subsequent eight months, with appearances on diffusion-weighted magnetic resonance imaging typical of sporadic Creutzfeldt-Jakob disease, which was confirmed pathologically at postmortem examination. While the presence of PNFA with speech apraxia is thought to predict underlying tauopathy, sporadic Creutzfeldt-Jakob disease may mimic this presentation and present in a highly circumscribed form not previously described.
    Alzheimer disease and associated disorders 06/2012; 27(4). DOI:10.1097/WAD.0b013e318260ab27 · 2.44 Impact Factor
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    ABSTRACT: Y. S. Davidson, A. C. Robinson, Q. Hu, M. Mishra, A. Baborie, E. Jaros, R. H. Perry, N. J. Cairns, A. Richardson, A. Gerhard, D. Neary, J. S. Snowden, E. H. Bigio and D. M. A. Mann (2013) Neuropathology and Applied Neurobiology39, 157–165 Nuclear carrier and RNA-binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes Aims: We aimed to investigate the role of the nuclear carrier and binding proteins, transportin 1 (TRN1) and transportin 2 (TRN2), TATA-binding protein-associated factor 15 (TAF15) and Ewing's sarcoma protein (EWS) in inclusion body formation in cases of frontotemporal lobar degeneration (FTLD) associated with fused in sarcoma protein (FTLD-FUS). Methods: Eight cases of FTLD-FUS (five cases of atypical FTLD-U, two of neuronal intermediate filament inclusion body disease and one of basophilic inclusion body disease) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. Ten cases of FTLD associated with TDP-43 inclusions served as reference cases. Results: The inclusion bodies in FTLD-FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP-43 aggregations in FTLD. Conclusions: Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP-43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements.
    Neuropathology and Applied Neurobiology 04/2012; 39(2). DOI:10.1111/j.1365-2990.2012.01274.x · 3.93 Impact Factor
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    ABSTRACT: Frontotemporal lobar degeneration (FTLD) is a highly familial neurodegenerative disease. It has recently been shown that the most common genetic cause of FTLD and amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion in C9ORF72. To investigate whether this expansion was specific to the FTLD/ALS disease spectrum, we genotyped the hexanucleotide repeat region of C9ORF72 in a large cohort of patients with Alzheimer's disease (AD). A normal range of repeats was found in all cases. We conclude that the hexanucleotide repeat expansion is specific to the FTLD/ALS disease spectrum.
    Neurobiology of aging 03/2012; 33(8):1846.e5-6. DOI:10.1016/j.neurobiolaging.2012.01.109 · 5.01 Impact Factor
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    ABSTRACT: Primary progressive aphasia is clinically heterogeneous. We report a patient, alias Don, with a novel form of progressive aphasia, characterised by deep dyslexia and dysgraphia and dissociated access to phonological and orthographic word forms. The hallmarks of deep dyslexia and dysgraphia were present early in the course and persisted over time. Writing was initially poorer than reading, but this reversed over time. There was a lack of concordance between reading and writing errors. Don benefited from a semantic mediation strategy to learn letter sounds, involving associating letters with a country name (e.g., A=Afghanistan). Remarkably, he continued to be able to generate those phonologically complex country names when no longer able to name or sound letters. Don's performance is compatible with a traditional dual-route account of deep dyslexia and dysgraphia. The findings have potential practical implications for speech and language therapy in progressive aphasia. Moreover, they illustrate both the remarkable specificity yet clinical diversity in presentation of progressive aphasia.
    Cortex 03/2012; 48(9):1234-9. DOI:10.1016/j.cortex.2012.02.010 · 5.13 Impact Factor

Publication Stats

3k Citations
346.32 Total Impact Points


  • 2005–2015
    • The University of Manchester
      • • Centre for Clinical and Cognitive Neurosciences
      • • Mental Health and Neurodegeneration Research Group
      • • Faculty of Medical and Human Sciences
      • • Neuroscience Research Group
      Manchester, England, United Kingdom
  • 2011–2014
    • Salford Royal NHS Foundation Trust
      Salford, England, United Kingdom
  • 2002
    • Lancaster University
      Lancaster, England, United Kingdom