Publications by authors named "David Neary"

74 Publications

Concordance between PCR-based extraction-free saliva and nasopharyngeal swabs for SARS-CoV-2 testing.

HRB Open Res 2021 30;4:85. Epub 2021 Jul 30.

School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.

: Saliva represents a less invasive alternative to nasopharyngeal swab (NPS) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection. SalivaDirect is a nucleic acid extraction-free method for detecting SARS-CoV2 in saliva specimens. Studies evaluating the concordance of gold standard NPS and newly developed SalivaDirect protocols are limited. The aim of our study was to to assess SalivaDirect as an alternative method for COVID-19 testing. : Matching NPS and saliva samples were analysed from a cohort of symptomatic (n=127) and asymptomatic (n=181) participants recruited from hospital and university settings, respectively. RNA was extracted from NPS while saliva samples were subjected to the SalivaDirect protocol before RT-qPCR analysis. The presence of SARS-Cov-2 was assessed using and gene targets in NPS and saliva, respectively. : Overall we observed 94.3% sensitivity (95% CI 87.2-97.5%), and 95.9% specificity (95% CI 92.4-97.8%) in saliva when compared to matching NPS samples. Analysis of concordance demonstrated 95.5% accuracy overall for the saliva test relative to NPS, and a very high level of agreement (κ coefficient = 0.889, 95% CI 0.833-0.946) between the two sets of specimens. Fourteen of 308 samples were discordant, all from symptomatic patients. Ct values were >30 in 13/14 and >35 in 6/14 samples. No significant difference was found in the Ct values of matching NPS and saliva sample ( =0.860). A highly significant correlation (r = 0.475, <0.0001) was also found between the Ct values of the concordant positive saliva and NPS specimens. : Use of saliva processed according to the SalivaDirect protocol represents a valid method to detect SARS-CoV-2. Accurate and less invasive saliva screening is an attractive alternative to current testing methods based on NPS and would afford greater capacity to test asymptomatic populations especially in the context of frequent testing.
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http://dx.doi.org/10.12688/hrbopenres.13353.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408542PMC
July 2021

Commentary for Sequential Therapy Based on Evolvement of Patterns: A New Model for Treatment of Alzheimer's Disease.

Chin J Integr Med 2019 08;25(8):563-564

Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Salford, UK.

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http://dx.doi.org/10.1007/s11655-019-3068-9DOI Listing
August 2019

Semantic dementia and the left and right temporal lobes.

Cortex 2018 10 31;107:188-203. Epub 2017 Aug 31.

Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, UK.

Semantic dementia, a circumscribed disorder of semantic knowledge, provides a unique model for understanding the neural basis for semantic representation. The study addressed areas of contention: the relative roles of the left and right temporal lobe, the contribution of anterior versus posterior temporal cortex and the status of the anterior temporal lobes as amodal hub. Naming and word comprehension was examined in 41 semantic dementia patients, 31 with left-predominant and 10 right-predominant atrophy. In keeping with expectation, naming and comprehension were significantly poorer in left-predominant patients. Structural magnetic resonance image analysis, using a visual rating scale, showed strong inverse correlations between naming scores and severity of both left anterior and posterior temporal lobe atrophy. By contrast, comprehension performance was more strongly correlated with left posterior temporal atrophy. Analysis of naming errors revealed a correlation between anterior temporal atrophy and associative/functional descriptive responses, implying availability of semantic information. By contrast, 'don't know' responses, indicative of loss of semantic knowledge, were linked to left posterior temporal lobe atrophy. Semantic errors, the hallmark of semantic dementia, were linked to right hemisphere atrophy, especially the right posterior temporal lobe. Matched visual-verbal tasks (famous face and name identification, Pyramids and Palm trees pictures and words, animal knowledge from 3-D models and animal names) administered to nine patients elicited variable correspondence between performance on nonverbal and verbal versions of the task. Marked performance dissociations were demonstrated in some patients: poorer understanding of names/words in left-predominant patients and of faces/pictures/models in right-predominant cases. The findings are compatible with the notion of the anterior temporal lobes as areas of convergence, but are less easily accommodated within the framework of amodal conceptual representation. The data, which reconcile some apparent contradictions in the literature, are discussed in the light of the nature and distribution of degenerative change in semantic dementia.
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http://dx.doi.org/10.1016/j.cortex.2017.08.024DOI Listing
October 2018

Examining the language and behavioural profile in FTD and ALS-FTD.

J Neurol Neurosurg Psychiatry 2017 08 8;88(8):675-680. Epub 2017 Jun 8.

Manchester Academic Health Sciences Centre, Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, UK.

Background: A proportion of patients with behavioural variant frontotemporal dementia (bvFTD) develop amyotrophic lateral sclerosis (ALS). It is currently unknown whether the behavioural and cognitive syndrome in bvFTD with ALS (ALS-FTD) is indistinguishable from that of bvFTD alone.

Methods: A retrospective cohort of 241 patients with clinical diagnoses of bvFTD (n=185) or ALS-FTD (n=56) was examined with respect to behavioural, cognitive and neuropsychiatric symptoms. Features were rated as present or absent based on information recorded from clinical interviews and detailed neuropsychological assessment.

Results: A number of behavioural and affective changes were reported more frequently in bvFTD than ALS-FTD: social disinhibition (p<0.001), inertia (p<0.001), loss of sympathy and empathy (p0.008), repetitive behaviours (p<0.001) and dietary changes (p<0.001). Warmth of affect demonstrated in the clinic setting was reported more often in ALS-FTD than bvFTD (p<0.001). Executive impairments occurred equally in both groups. Language impairments were more common in ALS-FTD than bvFTD: agrammatism (p<0.017) and impaired sentence comprehension (p<0.036). Psychotic features were relatively rare and did not distinguish the groups.

Conclusions: Our findings suggest differences between bvFTD and ALS-FTD. In particular, while changes in social behaviour are prominent in bvFTD alone, there may be a comparatively greater degree of language impairment in ALS-FTD. Prospective exploration of the pattern of differences between these groups will be essential. Identification of a distinct neuropsychological phenotype in ALS-FTD may have clinical implications for early diagnosis, disease management and care planning and theoretical implications for our understanding of the relationship between ALS and FTD.
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http://dx.doi.org/10.1136/jnnp-2017-315667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537548PMC
August 2017

Semantic dementia, progressive non-fluent aphasia and their association with amyotrophic lateral sclerosis.

J Neurol Neurosurg Psychiatry 2017 08 29;88(8):711-712. Epub 2017 May 29.

Cerebral Function Unit, Manchester Academic Health Sciences Centre, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, UK.

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http://dx.doi.org/10.1136/jnnp-2016-314912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537533PMC
August 2017

Co-Occurrence of Language and Behavioural Change in Frontotemporal Lobar Degeneration.

Dement Geriatr Cogn Dis Extra 2016 May-Aug;6(2):205-13. Epub 2016 Jun 1.

Manchester Academic Health Sciences Centre, Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, Manchester, UK; Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.

Background/objectives: We aimed to evaluate the co-occurrence of language and behavioural impairment in patients with frontotemporal lobar degeneration (FTLD) spectrum pathology.

Methods: Eighty-one dementia patients with pathological confirmation of FTLD were identified. Anonymized clinical records from patients' first assessment were rated for language and behavioural features from frontotemporal dementia consensus criteria, primary progressive aphasia (PPA) criteria and 1998 FTLD criteria.

Results: Over 90% of patients with FTLD pathology exhibited a combination of at least one behavioural and one language feature. Changes in language, in particular, were commonly accompanied by behavioural change. Notably, the majority of patients who displayed language features characteristic of semantic variant PPA exhibited 'early perseverative, stereotyped or compulsive/ritualistic behaviour'. Moreover, 'executive/generation deficits with relative sparing of memory and visuospatial functions' occurred in most patients with core features of non-fluent variant PPA.

Conclusion: Behavioural and language symptoms frequently co-occur in patients with FTLD pathology. Current classifications, which separate behavioural and language syndromes, do not reflect this co-occurrence.
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http://dx.doi.org/10.1159/000444848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913762PMC
June 2016

Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations.

Amyotroph Lateral Scler Frontotemporal Degener 2015 16;16(7-8):497-505. Epub 2015 Oct 16.

b Institute of Brain, Behaviour and Mental Health, Faculty of Human and Medical Sciences, University of Manchester , Manchester , UK.

Our objective was to compare the clinical and pathological characteristics of frontotemporal dementia patients with MAPT, GRN and C9orf72 gene mutations. We carried out a cross-sectional comparative study of 74 gene-positive patients (15 MAPT, 17 GRN and 42 C9orf72). Thirty had post mortem pathological data permitting clinico-pathological correlation. MAPT patients were younger than other groups, and showed more frequent behavioural disinhibition, repetitive and stereotyped behaviours, semantic impairment and temporal predominance of atrophy. GRN patients were older at death and more likely to present with non-fluent aphasia. C9orf72 patients alone showed a co-occurrence of ALS. They showed more psychotic symptoms and irrational behaviour, yet were more often reported clinically as socially appropriate and warm. They showed less dietary change than other groups. C9orf72 patients with and without ALS differed only in frequency of psychosis. Greater clinical overlap was observed between GRN and C9orf72 compared to MAPT cases. MAPT cases had tau and GRN and C9orf72, with one exception, TDP-43 pathology. Non-fluent aphasia was linked to TDP subtype A in both GRN and C9orf72 cases and ALS with subtype B. In conclusion, the findings reinforce clinical heterogeneity in FTD and strengthen evidence that genotype influences clinical presentation. Clinical features may inform targeted genetic testing.
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http://dx.doi.org/10.3109/21678421.2015.1074700DOI Listing
August 2016

Psychosis associated with expansions in the C9orf72 gene: the influence of a 10 base pair gene deletion.

J Neurol Neurosurg Psychiatry 2016 May 2;87(5):562-3. Epub 2015 Apr 2.

Faculty of Human and Medical Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.

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http://dx.doi.org/10.1136/jnnp-2015-310441DOI Listing
May 2016

Cognitive-behavioural features of progressive supranuclear palsy syndrome overlap with frontotemporal dementia.

J Neurol 2015 7;262(4):916-22. Epub 2015 Feb 7.

Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal NHS Foundation Trust, Stott Lane, Salford, M6 8HD, UK,

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.
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http://dx.doi.org/10.1007/s00415-015-7657-zDOI Listing
January 2016

18F-florbetapir PET in patients with frontotemporal dementia and Alzheimer disease.

J Nucl Med 2015 Mar 5;56(3):386-91. Epub 2015 Feb 5.

Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, United Kingdom

Unlabelled: Pathologic deposition of amyloid β (Aβ) protein is a key component in the pathogenesis of Alzheimer 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 controls and patients with AD and FTD.

Methods: Ten healthy controls (mean age ± SD, 62.5 ± 5.2 y), 10 AD patients (mean age ± SD, 62.6 ± 4.5), and 8 FTD patients (mean age ± SD, 62.5 ± 9.6) were recruited to the study. All patients underwent detailed clinical and neuropsychologic assessment and T1-weighted MR imaging and were genotyped for apolipoprotein E status. All participants underwent dynamic (18)F-florbetapir PET on a high-resolution research tomograph, and FTD patients also underwent (18)F-FDG PET scans. Standardized uptake value ratios (SUVRs) were extracted for predefined gray and white matter regions of interest using cerebellar gray matter as a reference region. Static PET images were evaluated by trained raters masked to clinical status and regional analysis.

Results: Total cortical gray matter (18)F-florbetapir uptake values were significantly higher in AD patients (median SUVR, 1.73) than FTD patients (SUVR, 1.13, P = 0.002) and controls (SUVR, 1.26, P = 0.04). (18)F-Florbetapir uptake was also higher in AD patients than FTD patients and controls in the frontal, parietal, occipital, and cingulate cortices and in the central subcortical regions. Only 1 FTD patient (homozygous for apolipoprotein E ε4) displayed high cortical (18)F-florbetapir retention, whereas (18)F-FDG PET demonstrated mesiofrontal hypometabolism consistent with the clinical diagnosis of FTD. Most visual raters classified 1 control (10%) and 8 AD (80%) and 2 FTD (25%) patients as amyloid-positive, whereas ratings were tied in another 2 FTD patients and 1 healthy control.

Conclusion: Cortical (18)F-florbetapir uptake is low in most FTD patients, providing good discrimination from AD. However, visual rating of FTD scans was challenging, with a higher rate of discordance between interpreters than in AD and control subjects.
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http://dx.doi.org/10.2967/jnumed.114.147454DOI Listing
March 2015

Plasma levels of progranulin and interleukin-6 in frontotemporal lobar degeneration.

Neurobiol Aging 2015 Mar 18;36(3):1603.e1-4. Epub 2014 Oct 18.

Faculty of Human and Medical Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK; Cerebral Function Unit, Department of Neurology, Greater Manchester Neuroscience Centre, Salford Royal Foundation Trust, Salford, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504979PMC
March 2015

p62/SQSTM1 analysis in frontotemporal lobar degeneration.

Neurobiol Aging 2015 Mar 18;36(3):1603.e5-9. Epub 2014 Oct 18.

Faculty of Medical and Human Sciences, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.08.035DOI Listing
March 2015

Semantic Corticobasal Dementia: Challenging Nosology in Frontotemporal Lobe Degeneration.

Alzheimer Dis Assoc Disord 2015 Oct-Dec;29(4):360-3

*Department of Clinical and Experimental Medicine, Polytechnic University of Marche †Nuclear Medicine Department, Ospedali Riuniti di Ancona, Ancona ‡Department of Psychology, Milano-Bicocca University, Milano, Italy §Mental Health and Neurodegeneration Research Group, University of Manchester, Manchester, UK.

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http://dx.doi.org/10.1097/WAD.0000000000000064DOI Listing
September 2016

Do NIA-AA criteria distinguish Alzheimer's disease from frontotemporal dementia?

Alzheimers Dement 2015 Feb 9;11(2):207-15. Epub 2014 Jul 9.

Manchester Academic Health Sciences Centre, Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, UK; Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jalz.2014.04.516DOI Listing
February 2015

Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease.

Neurobiol Aging 2014 Oct 2;35(10):2422.e13-6. Epub 2014 May 2.

University College London (UCL) Institute of Neurology, London, UK.

Early-onset Alzheimer's disease (EOAD) represents 1%-2% of the Alzheimer's disease (AD) cases, and it is generally characterized by a positive family history and a rapidly progressive symptomatology. Rare coding and fully penetrant variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the only causative mutations reported for autosomal dominant AD. Thus, in this study we used exome sequencing data to rapidly screen rare coding variability in APP, PSEN1, and PSEN2, in a British cohort composed of 47 unrelated EOAD cases and 179 elderly controls, neuropathologically proven. We report 2 novel and likely pathogenic variants in PSEN1 (p.L166V and p.S230R). A comprehensive catalog of rare pathogenic variants in the AD Mendelian genes is pivotal for a premortem diagnosis of autosomal dominant EOAD and for the differential diagnosis with other early onset dementias such as frontotemporal dementia (FTD) and Creutzfeldt-Jakob disease (CJD).
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4099516PMC
October 2014

Classification and pathology of primary progressive aphasia.

Neurology 2013 Nov 18;81(21):1832-9. Epub 2013 Oct 18.

From the Manchester Academic Health Sciences Centre (J.M.H., C.G., J.C.T., A.M.T.R., D.N., D.d.P., P.P., D.M.A.M., J.S.S., M.J.), Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford; and Institute of Brain, Behaviour and Mental Health (J.M.H., D.N., D.M.A.M., J.S.S., M.J.), University of Manchester, UK.

Objective: 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.

Methods: 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.

Results: 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).

Conclusion: 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.
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http://dx.doi.org/10.1212/01.wnl.0000436070.28137.7bDOI Listing
November 2013

History of a suspected delirium is more common in dementia with Lewy bodies than Alzheimer's disease: a retrospective study.

Int J Geriatr Psychiatry 2014 Feb 31;29(2):178-81. Epub 2013 May 31.

Department of Older Peoples Medicine, Newcastle upon Tyne hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK; Institute of Ageing and Health, Campus of Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.

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.

Results: In 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

Conclusions: A 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.
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http://dx.doi.org/10.1002/gps.3986DOI Listing
February 2014

Fear of crime and the environment: systematic review of UK qualitative evidence.

BMC Public Health 2013 May 24;13:496. Epub 2013 May 24.

Department of Social and Environmental Health Research, London School of Hygiene & Tropical Medicine, London, UK.

Background: The fear of crime may have negative consequences for health and wellbeing. It is influenced by factors in the physical and social environment. This study aimed to review and synthesize qualitative evidence from the UK on fear of crime and the environment.

Methods: Eighteen databases were searched, including crime, health and social science databases. Qualitative studies conducted in the UK which presented data on fear of crime and the environment were included. Quality was assessed using Hawker et al.'s framework. Data were synthesized thematically.

Results: A total of 40 studies were included in the review. Several factors in the physical environment are perceived to impact on fear of crime, including visibility and signs of neglect. However, factors in the local social environment appear to be more important as drivers of fear of crime, including social networks and familiarity. Broader social factors appear to be of limited relevance. There is considerable evidence for limitations on physical activity as a result of fear of crime, but less for mental health impacts.

Conclusions: Fear of crime represents a complex set of responses to the environment. It may play a role in mediating environmental impacts on health and wellbeing.
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http://dx.doi.org/10.1186/1471-2458-13-496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666893PMC
May 2013

Environmental interventions to reduce fear of crime: systematic review of effectiveness.

Syst Rev 2013 May 12;2:30. Epub 2013 May 12.

Department of Social and Environmental Health Research, London School of Hygiene & Tropical Medicine, 5-17 Tavistock Place, London, WC1H 9SH, UK.

Background: Fear of crime is associated with negative health and wellbeing outcomes, and may mediate some impacts of the built environment on public health. A range of environmental interventions have been hypothesized to reduce the fear of crime.

Methods: This review aimed to synthesize the literature on the effectiveness of interventions in the built environment to reduce the fear of crime. Systematic review methodology, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance, was used. Studies of environmental interventions which reported a fear of crime outcome and used any prospective evaluation design (randomized controlled trial (RCT), trial or uncontrolled before-and-after study) were included. Eighteen databases were searched. The Hamilton tool was used to assess quality. A narrative synthesis of findings was undertaken.

Results: A total of 47 studies were included, 22 controlled and 25 uncontrolled, with total sample sizes ranging from n = 52 to approximately n = 23,000. Thirty-six studies were conducted in the UK, ten studies in the USA and one study in the Netherlands. The quality of the evidence overall is low. There are some indications that home security improvements and non-crime-related environmental improvements may be effective for some fear of crime outcomes. There is little evidence that the following reduce fear of crime: street lighting improvements, closed-circuit television (CCTV), multi-component environmental crime prevention programs or regeneration programs.

Conclusions: There is some evidence for the effectiveness of specific environmental interventions in reducing some indicators of fear of crime, but more attention to the context and possible confounders is needed in future evaluations of complex social interventions such as these.
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http://dx.doi.org/10.1186/2046-4053-2-30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660218PMC
May 2013

Sensitivity and specificity of FTDC criteria for behavioral variant frontotemporal dementia.

Neurology 2013 May 17;80(20):1881-7. Epub 2013 Apr 17.

Manchester Academic Health Sciences Centre, Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, UK.

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.
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http://dx.doi.org/10.1212/WNL.0b013e318292a342DOI Listing
May 2013

Frontal lobe dementia, motor neuron disease, and clinical and neuropathological criteria.

J Neurol Neurosurg Psychiatry 2013 Jul 12;84(7):713-4. Epub 2013 Mar 12.

Manchester Academic Health Sciences Centre, Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK.

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http://dx.doi.org/10.1136/jnnp-2012-304549DOI Listing
July 2013

Frontotemporal dementia with amyotrophic lateral sclerosis: a clinical comparison of patients with and without repeat expansions in C9orf72.

Amyotroph Lateral Scler Frontotemporal Degener 2013 Apr 19;14(3):172-6. Epub 2013 Feb 19.

Manchester Academic Health Sciences Centre, Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Foundation Trust, Salford, UK.

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.
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http://dx.doi.org/10.3109/21678421.2013.765485DOI Listing
April 2013

Crime, fear of crime, environment, and mental health and wellbeing: mapping review of theories and causal pathways.

Health Place 2012 Jul 19;18(4):757-65. Epub 2012 Apr 19.

Department of Social and Environmental Health Research, London School of Hygiene & Tropical Medicine, 15-17 Tavistock Place, London WC1H 9SH, UK.

This paper presents the findings from a review of the theoretical and empirical literature on the links between crime and fear of crime, the social and built environment, and health and wellbeing. A pragmatic approach was employed, with iterative stages of searching and synthesis. This produced a holistic causal framework of pathways to guide future research. The framework emphasises that crime and fear of crime may have substantial impacts on wellbeing, but the pathways are often highly indirect, mediated by environmental factors, difficult to disentangle and not always in the expected direction. The built environment, for example, may affect health via its impacts on health behaviours; via its effects on crime and fear of crime; or via the social environment. The framework also helps to identify unexpected factors which may affect intervention success, such as the risk of adverse effects from crime prevention interventions as a result of raising awareness of crime.
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http://dx.doi.org/10.1016/j.healthplace.2012.04.001DOI Listing
July 2012

Progressive aphasia presenting with deep dyslexia and dysgraphia.

Cortex 2012 Oct 7;48(9):1234-9. Epub 2012 Mar 7.

Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal Foundation Trust, Salford, UK.

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.
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http://dx.doi.org/10.1016/j.cortex.2012.02.010DOI Listing
October 2012

Analysis of the hexanucleotide repeat in C9ORF72 in Alzheimer's disease.

Neurobiol Aging 2012 Aug 10;33(8):1846.e5-6. Epub 2012 Mar 10.

Mental Health and Neurodegeneration Research Group, Faculty of Human and Medical Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.

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.
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http://dx.doi.org/10.1016/j.neurobiolaging.2012.01.109DOI Listing
August 2012

Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations.

Brain 2012 Mar 2;135(Pt 3):693-708. Epub 2012 Feb 2.

Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal Foundation Trust, Salford, M6 8HD, UK.

The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients' clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients' delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all cases of frontotemporal dementia with motor neuron disease. Other mutations remain to be discovered. C9ORF72 mutations are associated with variable clinical presentations and pathology. Nevertheless, the findings highlight a powerful association between C9ORF72 mutations and psychosis and suggest that the behavioural characteristics of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.
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http://dx.doi.org/10.1093/brain/awr355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286329PMC
March 2012

Famous people knowledge and the right and left temporal lobes.

Behav Neurol 2012 ;25(1):35-44

Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal Foundation Trust, Salford, UK.

It is generally accepted that the anterior temporal lobes support knowledge of famous people. The specific roles of the right and left temporal lobe remain a subject of debate, with some studies suggesting differential roles based on modality (visual versus verbal information) and others category (person knowledge versus general semantics). The present study re-examined performance of semantic dementia patients with predominantly right and predominantly left temporal lobe atrophy on famous face, famous name and general semantic tasks, with the specific aim of testing the hypothesis that the right temporal lobe has a privileged role for person knowledge and the left temporal lobe for general semantic knowledge. Comparisons of performance rankings across tasks showed no evidence to support this hypothesis. By contrast, there was robust evidence from naming, identification and familiarity measures for modality effects: right-sided atrophy being associated with relatively greater impairment for faces and visual tasks and left-sided atrophy for names and verbal tasks. A double dissociation in test scores in two patients reinforced these findings. The data present a challenge for the influential `semantic hub' model, which views the anterior temporal lobes as an area of convergence in which semantic information is represented in amodal form.
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http://dx.doi.org/10.3233/BEN-2012-0347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294234PMC
May 2012

TDP-43 pathological changes in early onset familial and sporadic Alzheimer's disease, late onset Alzheimer's disease and Down's syndrome: association with age, hippocampal sclerosis and clinical phenotype.

Acta Neuropathol 2011 Dec 4;122(6):703-13. Epub 2011 Oct 4.

Mental Health and Neurodegeneration Research Group, Salford Royal Foundation Trust, University of Manchester, Salford M6 8HD, UK.

TDP-43 immunoreactive (TDP-43-ir) pathological changes were investigated in the temporal cortex and hippocampus of 11 patients with autosomal dominant familial forms of Alzheimer's disease (FAD), 169 patients with sporadic AD [85 with early onset disease (EOAD) (i.e before 65 years of age), and 84 with late onset after this age (LOAD)], 50 individuals with Down's Syndrome (DS) and 5 patients with primary hippocampal sclerosis (HS). TDP-43-ir pathological changes were present, overall, in 34/180 of AD cases. They were present in 1/11 (9%) FAD, and 9/85 (10%) EOAD patients but were significantly more common (p = 0.003) in LOAD where 24/84 (29%) patients showed such changes. There were no demographic differences, other than onset age, between AD patients with or without TDP-43-ir pathological changes. Double immunolabelling indicated that these TDP-43-ir inclusions were frequently ubiquitinated, but were only rarely AT8 (tau) immunoreactive. Only 3 elderly DS individuals and 4/5 cases of primary HS showed similar changes. Overall, 21.7% of AD cases and 6% DS cases showed hippocampal sclerosis (HS). However, only 9% FAD cases and 16% EOAD cases showed HS, but 29% LOAD cases showed HS. The proportion of EOAD cases with both TDP-43 pathology and HS tended to be greater than those in LOAD, where nearly half of all the cases with TDP-43 pathology did not show HS. The presence of TDP-43-ir changes in AD and DS may therefore be a secondary phenomenon, relating more to ageing than to AD itself. Nevertheless, a challenge to such an interpretation comes from the finding in AD of a strong relationship between TDP-43 pathology and cognitive phenotype. Patients with TDP-43 pathology were significantly more likely to present with an amnestic syndrome than those without (p < 0.0001), in keeping with pathological changes in medial temporal lobe structures. HS was also associated more commonly with an amnestic presentation (p < 0.005), but this association disappeared when TDP-43-positive cases were excluded from the analysis. TDP-43 may, after all, be integral to the pathology of AD, and to some extent determine the clinical phenotype present.
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http://dx.doi.org/10.1007/s00401-011-0879-yDOI Listing
December 2011
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