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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Challenges with Intestine and Multivisceral Re-Transplantation: Importance of Timing of Re-Transplantation and Optimal Immunosuppression.

BACKGROUND Patients undergoing re-transplantation often receive high doses of immunosuppression, which may lead to an immunocompromised status of the recipient. This study investigates the outcomes after intestine/multivisceral re-transplantation. MATERIAL AND METHODS Clinical outcomes of 23 patients undergoing 24 re-transplantations at a single intestine transplant center were reviewed. Bone marrow suppression was used as a surrogate marker of immunocompromised status, and was defined as platelet count <50 k/mm3 and absolute lymphocyte count <200/mm³. RESULTS All re-transplants except one were liver inclusive. Fifteen of 23 patients died at a median time of 12 months (range 0.2-75) after re-transplantation. Of the 15 deaths, nine (60%) resulted from complications associated with a compromised host immune status: graft versus host disease (GVHD) affecting bone marrow (three cases), persistent viral infection (three cases), post-transplant lymphoproliferative disorder (PTLD (one case), metastatic cancer (one case), multi-drug resistant polymicrobial sepsis (one case). Four deaths (27%) resulted from severe rejection. Non-survivors were more likely to have received alemtuzumab, and had higher incidence of bone marrow suppression. In addition to immunocompromised status and rejection, the use of alemtuzumab was associated with mortality after intestinal/multivisceral re-transplantation. CONCLUSIONS High mortality was associated with intestine/multivisceral re-transplantation. To improve clinical outcomes of intestine and multivisceral transplantation, it is important to allow reconstitution of host immunity. Longer interval between the two transplantations, and strategies such as allograft specific immunosuppression, may spare the host from the devastating effects of potent immunosuppression currently used.

The impact of ageing reveals distinct roles for human dentate gyrus and CA3 in pattern separation and object recognition memory.

Both recognition of familiar objects and pattern separation, a process that orthogonalises overlapping events, are critical for effective memory. Evidence is emerging that human pattern separation requires dentate gyrus. Dentate gyrus is intimately connected to CA3 where, in animals, an autoassociative network enables recall of complete memories to underpin object/event recognition. Despite huge motivation to treat age-related human memory disorders, interaction between human CA3 and dentate subfields is difficult to investigate due to small size and proximity. We tested the hypothesis that human dentate gyrus is critical for pattern separation, whereas, CA3 underpins identical object recognition. Using 3 T MR hippocampal subfield volumetry combined with a behavioural pattern separation task, we demonstrate that dentate gyrus volume predicts accuracy and response time during behavioural pattern separation whereas CA3 predicts performance in object recognition memory. Critically, human dentate gyrus volume decreases with age whereas CA3 volume is age-independent. Further, decreased dentate gyrus volume, and no other subfield volume, mediates adverse effects of aging on memory. Thus, we demonstrate distinct roles for CA3 and dentate gyrus in human memory and uncover the variegated effects of human ageing across hippocampal regions. Accurate pinpointing of focal memory-related deficits will allow future targeted treatment for memory loss.

Functional Cognitive Disorder: A Common Cause of Subjective Cognitive Symptoms.

Patients frequently present to the memory clinic with self-reported cognitive symptoms that cannot be attributed to structural, toxic, or metabolic causes, and are out of keeping with their performance on neuropsychological assessment. This can be considered to be Functional (psychosomatic) Cognitive Disorder, which results in significant patient distress and often has a major impact on social functioning and employment. We performed a retrospective analysis of the Bristol ReMemBr group cognitive clinic database to ascertain the prevalence of Functional Cognitive Disorder, review the patient characteristics, and develop new guidelines for diagnosis and management. 196 patients were screened of whom 23 were diagnosed with Functional Cognitive Disorder; the oldest patient with this diagnosis was aged 60 years at symptom onset. When considering only those presenting below the age of 60 years (total no. held on database = 69), a third were diagnosed with Functional Cognitive Disorder. On neuropsychological testing, 47% had an atypical (invalid) pattern of results, or failed tests of performance validity. Of those with valid neuropsychological results, 80% scored in the normal range. Depression and anxiety were common but did not appear to be the primary cause of cognitive symptoms. Particular characteristics seen were excessively low self-rating of memory ability, and discrepancies between perceived and actual cognitive performance. The rate of unemployment was high, often due to the cognitive symptomatology. This is an important disorder to address, being common in working adults, and carrying a risk of misdiagnosis as early neurodegeneration, with subsequent inappropriate treatment and inclusion in clinical trials.