Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

Precision oncology using ex vivo technology: a step towards individualised cancer care?

Despite advances in cancer genomics and the increased use of genomic medicine, metastatic cancer is still mostly an incurable and fatal disease. With diminishing returns from traditional drug discovery strategies, and high clinical failure rates, more emphasis is being placed on alternative drug discovery platforms, such as ex vivo approaches. Ex vivo approaches aim to embed biological relevance and inter-patient variability at an earlier stage of drug discovery, and to offer more precise treatment stratification for patients. However, these techniques also have a high potential to offer personalised therapies to patients, complementing and enhancing genomic medicine. Although an array of approaches are available to researchers, only a minority of techniques have made it through to direct patient treatment within robust clinical trials. Within this review, we discuss the current challenges to ex vivo approaches within clinical practice and summarise the contemporary literature which has directed patient treatment. Finally, we map out how ex vivo approaches could transition from a small-scale, predominantly research based technology to a robust and validated predictive tool. In future, these pre-clinical approaches may be integrated into clinical cancer pathways to assist in the personalisation of therapy choices and to hopefully improve patient experiences and outcomes.

Functional cognitive disorder: dementia's blind spot.

An increasing proportion of cognitive difficulties are recognized to have a functional cause, the chief clinical indicator of which is internal inconsistency. When these symptoms are impairing or distressing, and not better explained by other disorders, this can be conceptualized as a cognitive variant of functional neurological disorder, termed functional cognitive disorder (FCD). FCD is likely very common in clinical practice but may be under-diagnosed. Clinicians in many settings make liberal use of the descriptive term mild cognitive impairment (MCI) for those with cognitive difficulties not impairing enough to qualify as dementia. However, MCI is an aetiology-neutral description, which therefore includes patients with a wide range of underlying causes. Consequently, a proportion of MCI cases are due to non-neurodegenerative processes, including FCD. Indeed, significant numbers of patients diagnosed with MCI do not 'convert' to dementia. The lack of diagnostic specificity for MCI 'non-progressors' is a weakness inherent in framing MCI primarily within a deterministic neurodegenerative pathway. It is recognized that depression, anxiety and behavioural changes can represent a prodrome to neurodegeneration; empirical data are required to explore whether the same might hold for subsets of individuals with FCD. Clinicians and researchers can improve study efficacy and patient outcomes by viewing MCI as a descriptive term with a wide differential diagnosis, including potentially reversible components such as FCD. We present a preliminary definition of functional neurological disorder-cognitive subtype, explain its position in relation to other cognitive diagnoses and emerging biomarkers, highlight clinical features that can lead to positive diagnosis (as opposed to a diagnosis of exclusion), and red flags that should prompt consideration of alternative diagnoses. In the research setting, positive identifiers of FCD will enhance our recognition of individuals who are not in a neurodegenerative prodrome, while greater use of this diagnosis in clinical practice will facilitate personalized interventions.

Altered awareness of cognitive and neuropsychiatric symptoms in Parkinson's disease and Dementia with Lewy Bodies: A systematic review.

OBJECTIVES: Altered awareness of cognitive and neuropsychiatric symptoms is a common feature of neurodegeneration, which can significantly impact on quality of life, medication concordance and personal safety. Elucidating how awareness is affected by common alpha-synucleinopathies therefore has significant clinical relevance. We performed a systematic review of the literature on awareness of cognitive and neuropsychiatric symptoms in Parkinson's disease and Dementia with Lewy Bodies. METHODS: Searches of PubMed and Web of Science were carried out, using keywords and MeSH subheadings, limited to papers in English dealing with humans. The terms "Parkinson's" or "Lewy body" were used to denote the disease of interest, combined with either "agnosia", "anosognosia", "insight", "metacognition", or "neuropsychology" to denote the neuropsychological area of interest. RESULTS: 21 publications investigating awareness of cognitive symptoms, and 18 publications on awareness of neuropsychiatric symptoms were identified. The large majority focused on Parkinson's disease rather than Dementia with Lewy Bodies. Cognitively intact people with Parkinson's disease may over-report cognitive symptoms, whilst those with cognitive impairment under-report symptoms. Awareness of neuropsychiatric symptoms is likely to decline over time, particularly in those with progressive cognitive impairment. CONCLUSIONS: Altered awareness of cognitive and neuropsychiatric symptoms is common in Parkinson's disease. Symptom awareness varies significantly between individuals, and appears to be influenced by mood and global cognitive functioning, with executive functioning specifically implicated. There are gaps in our understanding of how dopaminergic medications influence symptom awareness, and a need for longitudinal studies of how awareness changes over time in Parkinson's disease and Dementia with Lewy Bodies.

Altered awareness of motor symptoms in Parkinson's disease and Dementia with Lewy Bodies: A systematic review.

OBJECTIVES: Altered awareness of motor symptoms is reported in people with Parkinson's disease and Dementia with Lewy Bodies, and may adversely affect quality of life and medication concordance. How symptom awareness is influenced by motor and cognitive disease severity, age and medication use is not fully understood. We carried out a systematic review of the literature on motor symptom awareness in Parkinson's disease and Dementia with Lewy Bodies. METHODS: Pubmed and Wed of Science were searched for relevant articles published in or prior to March 2019. Data regarding participant demographics, diagnosis, cognitive status, method of assessing awareness and study findings were extracted from relevant publications. RESULTS: Sixteen relevant publications were identified. Motor symptom awareness appears to decline over the course of Parkinson's disease. Imaging studies implicate the prefrontal cortex, with different mechanisms involved in hypokinesia and dyskinesia awareness. The hypothesis that people with right hemisphere based disease would have more severely reduced awareness is only weakly supported. Most studies focused on cognitively intact individuals, and on awareness of dyskinesia rather than hypokinesia. CONCLUSIONS: Whilst reduced awareness of dyskinesia and to a lesser extent hypokinesia is common, there is a lack of longitudinal data on how awareness changes over time, and how it interacts with global cognitive changes. Motor symptom awareness in Dementia with Lewy Bodies is understudied. Future studies of symptom awareness should include robust assessment of overall cognitive functioning, and use a longitudinal design to elucidate how awareness changes over time. J Am Geriatr Soc 68:-, 2020.

Tools for testing decision-making capacity in dementia.

Background: dementia is a common cause of altered decision-making capacity. Determining whether an individual has the ability to make a specific decision can be very challenging for both clinicians and researchers. The UK legislation requires that we both promote residual capacity where possible, and protect vulnerable adults who cannot make independent decisions. We evaluated published instruments designed to aid in the assessment of capacity, focussing on those meeting the UK legal requirements. We also consider further disease and culture-specific factors which may influence decision making. Methods: a search of electronic databases was made for articles published between 2000 and 2017 detailing structured tools for the assessment of mental capacity. These were evaluated against the UK legal requirements. Results: nine tools were identified which fulfilled the UK legal requirements. Their design and structure varied, as did the level of reliability and validity data available. Some instruments can be tailored for a specific decisional scenario, whilst others are designed for use by particular patient groups. Discussion: a wide range of mental capacity assessment instruments is available, but not all fulfil the UK legal requirements. Healthcare professionals and researchers should be mindful of personal, cultural and disease-specific factors when assessing capacity. No gold standard for capacity assessment exists, which hampers the evaluation of different approaches. A combination of the opinion of a healthcare professional or researcher trained in capacity evaluation, plus the use of a structured assessment tool is the most robust approach.

Functional cognitive disorder: what is it and what to do about it?

To err is human, and it is normal to make minor cognitive errors from time to time. Some people experience persistent subjective cognitive difficulties that cause distress and functional impairment, with no underlying structural, neurodegenerative, toxic or metabolic cause. This is considered a form of functional disorder. In this article, we review functional cognitive disorder and outline its core clinical features. Patients with this are typically of working age and have a source of psychological distress, such as chronic pain, work stress or family difficulties. Its distinction from incipient dementia is difficult and usually requires interval follow-up. Pointers towards possible dementia include abnormal neuroimaging or loss of insight. Many patients accept a functional cognitive disorder diagnosis and willingly engage with psychological therapies but there is no defined optimal treatment. Functional cognitive disorder is common but under-studied; future research priorities include the development of clear diagnostic criteria and robust trials of therapeutic strategies.

Inherited prion disease with 4-octapeptide repeat insertion: disease requires the interaction of multiple genetic risk factors.

Genetic factors are implicated in the aetiology of sporadic late-onset neurodegenerative diseases. Whether these genetic variants are predominantly common or rare, and how multiple genetic factors interact with each other to cause disease is poorly understood. Inherited prion diseases are highly heterogeneous and may be clinically mistaken for sporadic Creutzfeldt-Jakob disease because of a negative family history. Here we report our investigation of patients from the UK with four extra octapeptide repeats, which suggest that the risk of clinical disease is increased by a combination of the mutation and a susceptibility haplotype on the wild-type chromosome. The predominant clinical syndrome is a progressive cortical dementia with pyramidal signs, myoclonus and cerebellar abnormalities that closely resemble sporadic Creutzfeldt-Jakob disease. Autopsy shows perpendicular deposits of prion protein in the molecular layer of the cerebellum. Identity testing, PRNP microsatellite haplotyping and genealogical work confirm no cryptic close family relationships and suggests multiple progenitor disease haplotypes. All patients were homozygous for methionine at polymorphic codon 129. In addition, at a single nucleotide polymorphism upstream of PRNP thought to confer susceptibility to sporadic Creutzfeldt-Jakob disease (rs1029273), all patients were homozygous for the risk allele (combined P=5.9×10(-5)). The haplotype identified may also be a risk factor in other partially penetrant inherited prion diseases although it does not modify age of onset. Blood expression of PRNP in healthy individuals was modestly higher in carriers of the risk haplotype. These findings may provide a precedent for understanding apparently sporadic neurodegenerative diseases caused by rare high-risk mutations.

Metacognitive Performance on Memory and Visuospatial Tasks in Functional Cognitive Disorder.

Functional Cognitive Disorder (FCD) is a common diagnosis at the memory clinic. FCD is characterised by significant self-reported cognitive symptoms in the absence of external evidence of cognitive dysfunction. A potential explanation for this is a deficit in metacognition, the process by which we internally judge our own abilities. Here we investigated differences in accuracy, confidence, and metacognition between people with FCD (N = 20), neurodegenerative mild cognitive impairment (nMCI; N = 14), and healthy controls (N = 23). The groups were assessed on forced choice memory and perceptual tasks, with trial by trial confidence ratings. FCD and nMCI participants showed lower accuracy on the memory task (means FCD 63.65%, nMCI 63.96%, HC 71.22%), with a significant difference between the FCD and HC groups after controlling for age and sex. There were no between-group differences in memory task confidence (means FCD 3.19, nMCI 3.59, HC 3.71). The FCD group showed greater confidence when longer time was allowed on the memory task. No between group differences in perceptual task accuracy (means FCD 63.97%, nMCI 64.50%, FCD 65.86%) or confidence (means FCD 3.71, nMCI 3.43, HC 3.88) were found. No differences in metacognitive efficacy emerged between the groups, either on the memory or perceptual task (Memory Meta-d'/d':FCD 0.63, nMCI 0.94 HC 0.85; Perceptual Meta-d',d': FCD 0.50, nMCI 0.51, HC 0.72). Participants showed greater metacognitive efficacy on the memory task compared to the perceptual task. The difficulties experienced by people with FCD do not appear to be due to metacognitive deficits. Their performance was similar to people with nMCI over aspects of the memory tasks, which suggests that the primary issue may lie with memory encoding or retrieval, rather than with their judgement of performance accuracy.

Differentiating Functional Cognitive Disorder from Early Neurodegeneration: A Clinic-Based Study.

Functional cognitive disorder (FCD) is a relatively common cause of cognitive symptoms, characterised by inconsistency between symptoms and observed or self-reported cognitive functioning. We aimed to improve the clinical characterisation of FCD, in particular its differentiation from early neurodegeneration. Two patient cohorts were recruited from a UK-based tertiary cognitive clinic, diagnosed following clinical assessment, investigation and expert multidisciplinary team review: FCD, (n = 21), and neurodegenerative Mild Cognitive Impairment (nMCI, n = 17). We separately recruited a healthy control group (n = 25). All participants completed an assessment battery including: Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test Part B (TMT-B); Depression Anxiety and Stress Scale (DASS) and Minnesota Multiphasic Personality Inventory (MMPI-2RF). In comparison to healthy controls, the FCD and nMCI groups were equally impaired on trail making, immediate recall, and recognition tasks; had equally elevated mood symptoms; showed similar aberration on a range of personality measures; and had similar difficulties on inbuilt performance validity tests. However, participants with FCD performed significantly better than nMCI on HVLT-R delayed free recall and retention (regression coefficient -10.34, p = 0.01). Mood, personality and certain cognitive abilities were similarly altered across nMCI and FCD groups. However, those with FCD displayed spared delayed recall and retention, in comparison to impaired immediate recall and recognition. This pattern, which is distinct from that seen in prodromal neurodegeneration, is a marker of internal inconsistency. Differentiating FCD from nMCI is challenging, and the identification of positive neuropsychometric features of FCD is an important contribution to this emerging area of cognitive neurology.

Mixed neuropathology in frontotemporal lobar degeneration.

Aim: Frontotemporal lobar degeneration (FTLD) is a significant cause of dementia in mid-life and older adults. The extent of interactions between FTLD and other neurodegenerative pathologies is unclear. We reviewed the occurrences of mixed pathology in cases of neuropathologically diagnosed FTLD from the UK Brain Bank Network. Materials and methods: Clinicopathological details of cases of FTLD were extracted from the UK Brain Bank Network database. Results: Of 515 cases, 30.10% had mixed neuropathology. Concordance between clinical and neuropathological diagnosis was lower in these cases (38.71% vs. 59.17%). Alzheimer's spectrum pathology was the commonest additional finding. Age at death was higher in mixed neuropathology cases (mean 76.7 years vs. 72.59.0 years, p < 0.005), increasing in tandem with the number of neuropathologies present. Conclusion: Mixed neuropathology is common in FTLD and associated with increased age at death. Our findings suggest that mixed neuropathology influences age at onset and clinical phenotype in FTLD and makes accurate antemortem diagnosis more difficult. Further investigation of interactions between neuropathologies and phenotype is warranted, particularly in view of the potential impact on clinical diagnosis and patient selection for clinical trials.Key pointsMixed neurodegenerative neuropathologies commonly occur with frontotemporal lobar degeneration.The likelihood of mixed neuropathology with FTLD increases with older age at death.Mixed neuropathology could influence the clinical phenotype of frontotemporal lobar degeneration.

Fast Periodic Visual Stimulation indexes preserved semantic memory in healthy ageing.

Behavioural studies investigating the preservation of semantic memory in healthy ageing have reported mixed findings. One suggested reason for this discrepancy is that the processes underpinning lexical access to semantic knowledge may be sensitive to ageing. It is therefore necessary to assess semantic memory utilising tasks that are not explicitly linguistic. In this study, a fast periodic visual stimulation (FPVS) paradigm coupled with EEG was used to assess the ability of younger and older adults to automatically distinguish between images by their semantic category. Participants were presented with a 6 Hz stream of images drawn from one semantic category except every fifth image (occurring at a rate of 1.2 Hz) which was drawn from an alternate semantic category. For both younger and older adults, results demonstrate successful and comparable semantic categorisation. This was detectable at the individual level for 71% and 72% of older and younger adults, respectively. Given the rapid presentation rate and absence of explicit instruction to categorise images, the task is unlikely to utilise linguistic strategies and suggests the maintenance of semantic memory in healthy ageing. Moreover, this study utilised mobile EEG equipment and short presentation times that would be suitable for practical application outside a research setting.

PRNP variation in UK sporadic and variant Creutzfeldt Jakob disease highlights genetic risk factors and a novel non-synonymous polymorphism.

BACKGROUND: Genetic analysis of the human prion protein gene (PRNP) in suspect cases of Creutzfeldt-Jakob disease (CJD) is necessary for accurate diagnosis and case classification. Previous publications on the genetic variation at the PRNP locus have highlighted the presence of numerous polymorphisms, in addition to the well recognised one at codon 129, with significant variability between geographically distinct populations. It is therefore of interest to consider their influence on susceptibility or the clinico-pathological disease phenotype. This study aimed to characterise the frequency and effect of PRNP open reading frame polymorphisms other than codon 129 in both disease and control samples sourced from the United Kingdom population. METHODS: DNA was extracted from blood samples and genetic data obtained by full sequence analysis of the prion protein gene or by restriction fragment length polymorphism analysis using restriction enzymes specific to the gene polymorphism under investigation. RESULTS: 147 of 166 confirmed cases of variant CJD (vCJD) in the UK have had PRNP codon 129 genotyping and all are methionine homozygous at codon 129; 118 have had full PRNP gene sequencing. Of the latter, 5 cases have shown other polymorphic loci: at codon 219 (2, 1.69%), at codon 202 (2, 1.69%), and a 24 bp deletion in the octapeptide repeat region (1, 0.85%). E219K and D202D were not found in sporadic CJD (sCJD) cases and therefore may represent genetic risk factors for vCJD.Genetic analysis of 309 confirmed UK sCJD patients showed codon 129 genotype frequencies of MM: 59.5% (n = 184), MV: 21.4% (n = 66), and VV: 19.1% (n = 59). Thirteen (4.2%) had the A117A polymorphism, one of which also had the P68P polymorphism, four (1.3%) had a 24 bp deletion, and a single patient had a novel missense variation at codon 167. As the phenotype of this latter case is similar to sCJD and in the absence of a family history of CJD, it is unknown whether this is a form of genetic CJD, or simply a neutral polymorphism. CONCLUSIONS: This analysis of PRNP genetic variation in UK CJD patients is the first to show a comprehensive comparison with healthy individuals (n = 970) from the same population, who were genotyped for the three most common variations (codon 129, codon 117, and 24 bp deletion). These latter two genetic variations were equally frequent in UK sCJD or vCJD cases and a normal (healthy blood donor) UK population.

Functional Cognitive Disorder: Diagnostic Challenges and Future Directions.

Functional cognitive disorder describes patients with persistent, troublesome subjective cognitive complaints that are inconsistent with a recognized disease process, and where significant discrepancies are found between subjective and objectively observed cognitive functioning. The etiology is heterogeneous and potentially related to underlying psychological factors. Making a diagnosis of functional cognitive disorder can be challenging and there is the potential for misdiagnosis of early-stage neurodegeneration. We compared neuropsychological findings in three groups: functional cognitive disorder (FCD), mild cognitive impairment (MCI), and healthy controls. Participants were recruited from the ReMemBr Group Clinic, North Bristol NHS Trust, and via Join Dementia Research. Both the FCD and MCI groups showed elevated prospective and retrospective memory symptom scores. Performance on the Montreal cognitive assessment was equivalent in the FCD and MCI groups, both being impaired compared with the controls. The FCD group was younger than those with MCI. We discuss challenges and controversies in the diagnosis of functional cognitive disorder, alongside illustrative cases and proposals for areas of research priority.

Diagnostic accuracy of frontotemporal dementia. An artificial intelligence-powered study of symptoms, imaging and clinical judgement.

PURPOSE: Frontotemporal dementia (FTD) is a neurodegenerative disorder associated with a poor prognosis and a substantial reduction in quality of life. The rate of misdiagnosis of FTD is very high, with patients often waiting for years without a firm diagnosis. This study investigates the current state of the misdiagnosis of FTD using a novel artificial intelligence-based algorithm. PATIENTS & METHODS: An artificial intelligence algorithm has been developed to retrospectively analyse the patient journeys of 47 individuals diagnosed with FTD (age range 52-80). The algorithm analysed the efficiency of patient pathways by utilizing a reward signal of ‒1 to +1 to assess the symptoms, imaging techniques, and clinical judgement in both behavioural and language variants of the disease. RESULTS: On average, every patient was subjected to 4.93 investigations, of which 67.4% were radiological scans. From first presentation it took on average 939 days for a firm diagnosis. The mean time between appointments was 204 days, and the average patient had their diagnosis altered 7.37 times during their journey. The algorithm proposed improvements by evaluating the interventions that resulted in a decreased reward signal to both the individual and the population as a whole. CONCLUSIONS: The study proves that the algorithm can efficiently guide clinical practice and improve the accuracy of the diagnosis of FTD whilst making the process of auditing faster and more economically viable.

Neural correlates of altered insight in frontotemporal dementia: a systematic review.

Altered insight into disease or specific symptoms is a prominent clinical feature of frontotemporal dementia (FTD). Understanding the neural bases of insight is crucial to help improve FTD diagnosis, classification and management. A systematic review to explore the neural correlates of altered insight in FTD and associated syndromes was conducted. Insight was fractionated to examine whether altered insight into different neuropsychological/behavioural objects is underpinned by different or compatible neural correlates. 6 databases (Medline, Embase, PsycINFO, Web of Science, BIOSIS and ProQuest Dissertations & Theses Global) were interrogated between 1980 and August 2019. 15 relevant papers were found out of 660 titles screened. The studies included suggest that different objects of altered insight are associated with distinctive brain areas in FTD. For example, disease unawareness appears to predominantly correlate with right frontal involvement. In contrast, altered insight into social cognition potentially involves, in addition to frontal areas, the temporal gyrus, insula, parahippocampus and amygdala. Impaired insight into memory problems appears to be related to the frontal lobes, postcentral gyrus, parietal cortex and posterior cingulate. These results reflect to a certain extent those observed in other neurodegenerative conditions like Alzheimer's disease (AD) and also other brain disorders. Nevertheless, they should be cautiously interpreted due to variability in the methodological aspects used to reach those conclusions. Future work should triangulate different insight assessment approaches and brain imaging techniques to increase the understanding of this highly relevant clinical phenomenon in dementia.

Occurrence and expression of gene transfer agent genes in marine bacterioplankton.

Genes with homology to the transduction-like gene transfer agent (GTA) were observed in genome sequences of three cultured members of the marine Roseobacter clade. A broader search for homologs for this host-controlled virus-like gene transfer system identified likely GTA systems in cultured Alphaproteobacteria, and particularly in marine bacterioplankton representatives. Expression of GTA genes and extracellular release of GTA particles ( approximately 50 to 70 nm) was demonstrated experimentally for the Roseobacter clade member Silicibacter pomeroyi DSS-3, and intraspecific gene transfer was documented. GTA homologs are surprisingly infrequent in marine metagenomic sequence data, however, and the role of this lateral gene transfer mechanism in ocean bacterioplankton communities remains unclear.

Visual rating assessment of cerebral atrophy and its relationship with cognitive function in chronic obstructive pulmonary disease.

INTRODUCTION: Widespread white matter damage and cognitive impairment have been demonstrated in chronic obstructive pulmonary disease (COPD). However, it remains unclear if brain atrophy is a global phenomenon or if specific subregions are differentially affected. The aims of this study are, first, to test a simple, validated visual analogue grading technique. Second, we hypothesised that frontal regions of the brains of patients with COPD will show greater signs of atrophy compared with control subjects. Third, any localised regions of atrophy would correlate with components of cognitive performance. Finally, the severity of cerebral atrophy would be associated with measures of respiratory disease severity. METHODS: We used a simple, validated visual analogue grading technique to assess the degree of regional atrophy in multiple brain regions from cerebral MR images in patients with stable non-hypoxaemic COPD (n=25) and age-matched control subjects (n=25). We also explored correlations between regional brain atrophy with demographics, cognitive performance measures and disease severity. Measures of cognitive performance focused on executive function, working memory, verbal memory, overall memory and processing speed. Measures of disease severity include lung function, gas exchange, health status and breathlessness questionnaires. RESULTS: The visual grading scale found that patients with COPD had significantly greater frontal atrophy than control subjects (p=0.02), independent of smoking history, comorbid depression or anxiety. Cognitive function was significantly worse in the COPD group for executive function (p<0.001), working memory (p=0.02), verbal memory (p=0.03) and processing speed (p=0.001). Group differences in atrophy did not appear to account for differences in cognitive function. We were unable to identify meaningful correlations between regional atrophy and disease severity or cognitive function. CONCLUSION: Further work is needed to identify causative mechanisms behind unexplained structural brain changes in COPD.