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.

Predictors and prognosis of population-based subjective cognitive decline: longitudinal evidence from the Caerphilly Prospective Study (CaPS).

OBJECTIVES: To understand associations between the subjective experience of cognitive decline and objective cognition. This subjective experience is often conceptualised as an early step towards neurodegeneration, but this has not been scrutinised at the population level. An alternative explanation is poor meta-cognition, the extreme of which is seen in functional cognitive disorder (FCD). DESIGN: Prospective cohort (Caerphilly Prospective Study). SETTING: Population-based, South Wales, UK. PARTICIPANTS: This men-only study began in 1979; 1225 men participated at an average age of 73 in 2002-2004, including assessments of simple subjective cognitive decline (sSCD, defined as a subjective report of worsening memory or concentration). Dementia outcomes were followed up to 2012-2014. Data on non-completers was additionally obtained from death certificates and local health records. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was incident dementia over 10 years. Secondary outcome measures included prospective change in objective cognition and cross-sectional cognitive internal inconsistency (the existence of a cognitive ability at some times, and its absence at other times, with no intervening explanatory factors except for focus of attention). RESULTS: sSCD was common (30%) and only weakly associated with prior objective cognitive decline (sensitivity 36% (95% CI 30 to 42) and specificity 72% (95% CI 68 to 75)). Independent predictors of sSCD were older age, poor sleep quality and higher trait anxiety. Those with sSCD did not have excess cognitive internal inconsistency, but results suggested a mild attentional deficit. sSCD did not predict objective cognitive change (linear regression coefficient -0.01 (95% CI -0.13 to 0.15)) nor dementia (odds ratio 1.35 (0.61 to 2.99)) 10 years later. CONCLUSIONS: sSCD is weakly associated with prior objective cognitive decline and does not predict future cognition. Prior sleep difficulties and anxiety were the most robust predictors of sSCD. sSCD in the absence of objective decline appears to be a highly prevalent example of poor meta-cognition (ie, poor self-awareness of cognitive performance), which could be a driver for later FCD.

Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling long-term condition of unknown cause. The National Institute for Health and Care Excellence (NICE) published a guideline in 2021 that highlighted the seriousness of the condition, but also recommended that graded exercise therapy (GET) should not be used and cognitive-behavioural therapy should only be used to manage symptoms and reduce distress, not to aid recovery. This U-turn in recommendations from the previous 2007 guideline is controversial.We suggest that the controversy stems from anomalies in both processing and interpretation of the evidence by the NICE committee. The committee: (1) created a new definition of CFS/ME, which 'downgraded' the certainty of trial evidence; (2) omitted data from standard trial end points used to assess efficacy; (3) discounted trial data when assessing treatment harm in favour of lower quality surveys and qualitative studies; (4) minimised the importance of fatigue as an outcome; (5) did not use accepted practices to synthesise trial evidence adequately using GRADE (Grading of Recommendations, Assessment, Development and Evaluations trial evidence); (6) interpreted GET as mandating fixed increments of change when trials defined it as collaborative, negotiated and symptom dependent; (7) deviated from NICE recommendations of rehabilitation for related conditions, such as chronic primary pain and (8) recommended an energy management approach in the absence of supportive research evidence.We conclude that the dissonance between this and the previous guideline was the result of deviating from usual scientific standards of the NICE process. The consequences of this are that patients may be denied helpful treatments and therefore risk persistent ill health and disability.

Peripheral neuropathy secondary to a 'domino' liver transplant: a case report.

BACKGROUND: Peripheral neuropathy caused by amyloidosis is one of the well-recognised sequelae of mutations in the transthyretin gene (TTR). CASE PRESENTATION: We describe a case of peripheral neuropathy in a White British 74 year old man with wild-type TTR, 8 years following receipt of a 'domino' liver transplant (from a donor with a TTR mutation). The clinical phenotype and neurophysiology, coupled with presence of ATTR amyloid deposits on fat biopsy, established the diagnosis of ATTR amyloid neuropathy, as a consequence of receipt of a variant-TTR secreting liver. A nerve biopsy was not clinically appropriate for this patient. Such cases are rare since recipients of such livers are typically restricted to people whose natural lifespan is unlikely to stretch into the anticipated symptomatic period of ATTR amyloidosis. However, novel "gene silencing" therapeutics are now available which can dramatically alter the course of this disorder, by reducing the proportion of abnormal proteins. CONCLUSIONS: This represents a rare but predictable iatrogenic side effect, and doctors should be aware of this eventuality occurring in a shorter time span than previously anticipated.

Functional neurological disorder is a feminist issue.

Functional neurological disorder (FND) is a common and disabling disorder, often misunderstood by clinicians. Although viewed sceptically by some, FND is a diagnosis that can be made accurately, based on positive clinical signs, with clinical features that have remained stable for over 100 years. Despite some progress in the last decade, people with FND continue to suffer subtle and overt forms of discrimination by clinicians, researchers and the public. There is abundant evidence that disorders perceived as primarily affecting women are neglected in healthcare and medical research, and the course of FND mirrors this neglect. We outline the reasons why FND is a feminist issue, incorporating historical and contemporary clinical, research and social perspectives. We call for parity for FND in medical education, research and clinical service development so that people affected by FND can receive the care they need.

Recurrent depression has persistent effects on cognition but this does not appear to be mediated by neuroinflammation.

BACKGROUND: Later-life depression appears to be different to depression in younger adults. The underlying pathology may also differ. Depression is linked to dementia but whether it is a risk factor or an early sign of a developing dementia remains unclear. Neuroinflammation is increasingly recognised in both depression and Alzheimer's Disease. AIMS: To investigate the link between depression, inflammation and dementia. We hypothesised that recurrent depression has adverse effects on performance in cognitive tests in middle to older age and that this effect is modified by anti-inflammatory medication. METHODS: We identified UK based cohort studies which included individuals aged >50, had medical information, results from detailed cognitive testing and had used reliable measures to assess depression. Individuals with recurrent depression had ≥ 2 episodes of depression. Controls had no history of depression. The presence/absence of inflammatory illness was assessed using a standardised list of inflammatory conditions. Individuals with dementia, chronic neurological and psychotic conditions were excluded. Logistic and linear regression were used to examine the effect of depression on cognitive test performance and the mediating effect of chronic inflammation. RESULTS: Unexpectedly in both studies there was evidence that those with recurrent depression performed better in some cognitive tasks (e.g Mill Hill vocabulary) but worse in others (e.g. reaction time). In UK Biobank there was no evidence that anti-inflammatories moderated this effect. LIMITATIONS: Cross-sectional assessment of cognition. CONCLUSIONS: Although previous recurrent depression has small effects on cognitive test performance this does not appear to be mediated by chronic inflammatory disease.

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.

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.

The prevalence and correlates of alcohol use and alcohol use disorders: a population based study in Colombo, Sri Lanka.

BACKGROUND: Alcohol use is increasing in non-Western countries. However, the effects of this increase on the prevalence of alcohol use disorders (AUD) remains unknown, particularly in South Asia. This study aimed to estimate the prevalence of alcohol use and AUD in the Colombo District, Sri Lanka. Environmental risk factors and psychiatric correlates were also examined. METHODS: The Composite International Diagnostic Interview was used to assess alcohol use and psychiatric disorders in a population based sample of 6014 twins and singletons in the Colombo region of Sri Lanka. RESULTS: Lifetime alcohol use on 12 or more occasions was estimated at 63.1 % (95 % CI: 61.3-64.9) in men and 3.7 % (95 % CI: 3.0-4.3) in women. Prevalence of lifetime alcohol abuse and alcohol dependence in men was 6.2 % (95 % CI: 5.3-7.1) and 4.0 % (95 % CI: 3.3-4.7) respectively. Lower standard of living was independently associated with alcohol use and dependence but not abuse. Significant associations between lifetime AUD and other psychiatric disorders were observed. CONCLUSIONS: Lower prevalence of alcohol use and AUD was observed compared to Western countries. Prevalence of alcohol use and AUD were higher than previous reports. Socio-demographic and environmental risk factors appear to be similar across cultures as were associations between AUD and other psychiatric disorders.

Genetic and environmental etiology of nicotine use in Sri Lankan male twins.

Little is known about the prevalence and etiology of tobacco use in Asian populations. This study aims to test whether the finding of substantial heritability for tobacco-related phenotypes in Western populations is generalizable to developing countries. The twin method was used to estimate the relative contribution of genetic and environmental influences on nicotine-related phenotypes. Participants were selected from the population based Sri Lankan Twin Registry. The Composite International Diagnostic Interview was administered to 1,804 male individuals to assess five phenotypes: nicotine use; desire and unsuccessful attempts to quit smoking; subjective feeling of being tobacco dependent; and two DSM-IV diagnoses; nicotine dependence and nicotine withdrawal. Almost one-third of the male twins were life-time smokers. The genetic results were consistent with the previously reported findings from Western and Chinese populations, in that the nicotine use traits were significantly heritable, with environmental influences being of the non-shared nature. The results derived from the Causal Contingent Common pathway model (CCC) supported previous findings that show that liabilities to regular smoking and subsequent problem smoking have both shared and specific genetic influences.

Genetic and environmental contributions to the overlap between psychological, fatigue and somatic symptoms: a twin study in Sri Lanka.

BACKGROUND: Somatic symptoms often co-occur with psychological symptoms but this overlap is poorly understood. Some aspects of this overlap differ in the South Asian context, but it is not clear whether this is a reporting effect or an underlying difference in experienced illness. METHODS: Home interviews were administered to 4,024 twins randomly selected from a population-based twin register in the Colombo district of Sri Lanka (the CoTASS study). These included assessments of psychological, somatic and fatigue symptoms. The data were analyzed using factor analytic and quantitative genetic approaches. RESULTS: Confirmatory factor analysis showed that the symptoms from the three scales represented three separate dimensions, rather than all tapping into a single dimension. However, familial correlations among the data were most consistent with a common pathway model. This implies that a portion of the underlying vulnerability is common across psychological, fatigue and somatic symptoms. There were sex differences in the etiology of this model, with shared environmental and genetic influences playing different roles in men and women. CONCLUSIONS: There is a complex etiological relationship between psychological, fatigue and somatic symptoms. This is similar in Sri Lanka to Western countries, but there may be a greater influence from the family environment, suggesting that care needs to be taken when generalizing research findings between countries. People who complain of certain fatigue or somatic symptoms may well also have psychological symptoms, or may have genetic or environmental vulnerabilities to such problems.

Aetiology of fatigue in Sri Lanka and its overlap with depression.

BACKGROUND: Fatigue is a common symptom in Western high-income countries but is often medically unexplained and little is known about its presentation in other populations. AIMS: To explore the epidemiology and aetiology of fatigue in Sri Lanka, and of its overlap with depression. METHOD: A total of 4024 randomly selected twins from a population-based register in Sri Lanka (Colombo district) completed home interviews including the Chalder Fatigue Questionnaire. RESULTS: The prevalence of fatigue was similar to that in other countries, although prolonged fatigue may be less common. There was substantial comorbidity with a screen for lifetime depression. Non-shared environmental factors made the largest contributions, although genetic/family factors also contributed. The aetiology appeared consistent across the spectrum of severity. CONCLUSIONS: The aetiology of fatigue is broadly similar in Sri Lanka and Western high-income countries. Abnormal experiences of fatigue appear to be the extreme form of more common fatigue, rather than representing independent entities with different genetic or environmental risk factors.

Environmental exposures and their genetic or environmental contribution to depression and fatigue: a twin study in Sri Lanka.

BACKGROUND: There is very little genetically informative research identifying true environmental risks for psychiatric conditions. These may be best explored in regions with diverse environmental exposures. The current study aimed to explore similarities and differences in such risks contributing to depression and fatigue. METHODS: Home interviews assessed depression (lifetime-ever), fatigue and environmental exposures in 4,024 randomly selected twins from a population-based register in the Colombo district of Sri Lanka. RESULTS: Early school leaving and standard of living showed environmentally-mediated effects on depression, in men. In women, life events were associated with depression partly through genetic pathways (however, the temporal order is consistent with life events being an outcome of depression, as well as the other way around). For fatigue, there were environmentally mediated effects (through early school leaving and life events) and strong suggestions of family-environmental influences. CONCLUSIONS: Compared to previous studies from higher-income countries, novel environmentally-mediated risk factors for depression and fatigue were identified in Sri Lanka. But as seen elsewhere, the association between life events and depression was partially genetically mediated in women. These results have implications for understanding environmental mechanisms around the world.

Epidemiology and symptomatology of depression in Sri Lanka: a cross-sectional population-based survey in Colombo District.

BACKGROUND: It is important to understand the nature of depression in non-Western and lower-income countries, but little such research exists. This study aimed to examine the characteristic features of depression in Sri Lanka, and to identify environmental risk factors. METHODS: Depression diagnoses, symptoms and impairment were measured using the Composite International Diagnostic Interview, in a population-based sample of 6014 twins and non-twins in the Colombo region of Sri Lanka (the CoTASS sample). Socio-demographic factors and environments were assessed via questionnaires. RESULTS: Lifetime-ever depression was reported in 6.6% of participants, rising to 11.2% if the functional impairment criterion was excluded. The symptom profile of depression and its socio-demographic associations were very comparable to those in Western and more economically developed countries, whether functional impairment was included in the definition or not. Standard of living was independently associated with depression, especially among men at the more deprived end of the distribution. Specific associations were found with both financial wellbeing and material characteristics of the home environment. LIMITATIONS: The observational associations identified are cross-sectional, so do not necessarily imply causal links. CONCLUSIONS: Aside from a lower prevalence, depression is very similar in this predominantly urban Sri Lankan sample to higher-income, Western countries, and may be under-identified due to a relatively low cultural appropriateness of the assessment of impairment. Under Sri Lanka's cultural and environmental context, certain aspects of the material environment are associated with depression among certain segments of society, perhaps because of their particular link to social status and social networks.

Genetic and environmental contributions to depression in Sri Lanka.

BACKGROUND: Susceptibility to depression results from genetic and non-familially shared environmental influences in high-income, Western countries. Environments may play a different role for populations in different contexts. AIMS: To examine heritability of depression in the first large, population-based twin study in a low-income country. METHOD: Lifetime depression and a broader measure of depression susceptibility (D-probe) were assessed in 3908 adult twins in Sri Lanka (the CoTASS study). RESULTS: There were gender differences for the broad definition (D-probe), with a higher genetic contribution in females (61%) than males (4%). Results were similar for depression, but the prevalence was too low to estimate heritability for males. CONCLUSIONS: Genetic influences on depression in women appear to be at least as strong in this Sri Lankan sample as in higher-income countries. Conclusions are less clear for men but suggest a larger role for environments rather than genes. The nature as well as the magnitude of environmental influences may also differ across populations.

Genetic overlap between measures of hyperactivity/inattention and mood in children and adolescents.

OBJECTIVE: Evidence suggests that there is substantial comorbidity between attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder in childhood and adolescence. This study aims to investigate the degree to which etiological factors are shared between the symptoms of these significantly heritable disorders. METHOD: A twin study design was used to determine to what extent the covariation between the traits of ADHD and depression is genetically or environmentally mediated, based on parental reports. A general community sample of 645 twin pairs aged 5 to 17 years from the Cardiff Study of All Wales and North England Twins project took part in the study. Parent-rated measures of hyperactivity/inattention (Abbreviated Conners Hyperactivity subscale) and depression (Short Mood and Feelings Questionnaire). RESULTS: Phenotypes derived from the scales were significantly correlated in both boys and girls. Bivariate structural equation modeling revealed a large overlap in underlying genetic factors (boys, rA = 0.77; girls, rA = 0.67) along with a smaller influence of nonshared environment. CONCLUSIONS: These findings suggest that there are common genes conferring liability to both hyperactive/inattentive and depressive traits in children and adolescents. This has implications for future molecular genetic research into ADHD and major depressive disorder. Additionally, it indicates that the comorbid clinical presentation of these disorders may reflect a common genetic pathway.

Association of the dystrobrevin binding protein 1 gene (DTNBP1) in a bipolar case-control study (BACCS).

Recent studies suggest a degree of overlap in genetic susceptibility across the traditional categories of schizophrenia and bipolar disorder. There is some evidence for an association of the dystrobrevin binding protein 1 gene (DTNBP1) with schizophrenia, and, thus, this gene has also become a focus of further investigation in bipolar disorder (BD). The aim of our study is to explore the association of DTNBP1 with BD and with a sub phenotype, presence/absence of psychotic symptoms, in a sample of 515 patients with BD (ICD10/DSMIV) and 1,316 ethnically matched control subjects recruited from the UK. Seven DTNBP1 SNPs: rs2743852 (SNP C), rs760761 (P1320), rs1011313 (P1325), rs3213207 (P1635), rs2619539 (P1655), rs16876571 and rs17470454 were investigated using the SNPlex genotyping system and 1 SNP (rs2619522) genotypes were imputed. Association analyses were conducted in a sample of 452 cases and 956 controls. We found significant differences in genotypic and allelic frequencies of rs3213207 and rs760761 of DTNBP1 between bipolar patients and controls. We also showed a global haplotypic association and an association of a particular haplotype with BD. Our results are consistent with previous studies in term of a general association between DTNBP1 and bipolar disorder and provide additional evidence that a portion of the genotypic overlap between schizophrenia and bipolar affective disorder is attributable to this gene.

Colombo Twin and Singleton Study (CoTASS): a description of a population based twin study of mental disorders in Sri Lanka.

BACKGROUND: The Sri Lankan twin registry is one of the first to be established in a developing country, and its design has ensured sampling from a wide range of environmental conditions. It thus has great potential to examine environmental and genetic influences on diverse phenotypes, including psychiatric disorders, in the context of a diversity of environmental exposures, which may not have been fully explored in previous twin studies in developed countries. This paper presents the rationale for the study, describes its context, and the methods for twin ascertainment and data collection. METHODS: A population-based twin register was established in the Colombo district of Sri Lanka using infrastructure designed to periodically update the electoral register. We invited a subsample from this register to participate in the project on common mental disorders, using random ascertainment. A separate non-twin sample was randomly selected from the geographical areas where twins were found. Home interviewers collected diagnostic information on common mental disorders, as well as environmental exposures including life events, socio-economic conditions, and the impact of the civil war and the Tsunami of 2004. RESULTS: We identified 19,302 individuals in the creation of the population based twin register. We randomly selected a subsample, of whom 4,387 were eligible to participate and 4,024 agreed to be interviewed (including data on 1,954 complete pairs of twins and 5 sets of triplets). Those who refused consent had a similar mean age and sex ratio to those who were interviewed. We invited 2,485 singletons to participate and 2,019 were interviewed. CONCLUSION: Initial exploration of the data suggests the samples are very representative of the Colombo district of Sri Lanka, so we have created a unique resource for understanding the influences on mental disorders in developing countries, and to compare to the influences found in developed countries.