Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series.

Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.

The impact of regional 99mTc-HMPAO single-photon-emission computed tomography (SPECT) imaging on clinician diagnostic confidence in a mixed cognitive impairment sample.

AIM: To assess the clinical impact of regional cerebral blood flow (rCBF) single-photon-emission computed tomography (SPECT) imaging on diagnosis and clinician diagnostic confidence in a cohort of individuals with cognitive impairment. MATERIALS AND METHODS: Forty-one clinicians who referred 79 patients for a [99mTc]-hexamethylpropyleneamine oxime (HMPAO) SPECT for cognitive complaints completed a two-part questionnaire to determine the diagnosis and diagnostic confidence (using a 0-100 visual analogue scale [VAS]) before and after imaging. SPECT images were analysed using statistical parametric mapping and interpreted semi-quantitatively. Clinicians were also asked directly for their opinion on whether the imaging contributed to their diagnostic process. RESULTS: Diagnosis changed after imaging in 44% of cases, and confidence was significantly improved (VAS score change= +26.3±22.2) after imaging in cases where the pre-imaging confidence was low (p<0.001). Clinician confidence was not significantly different (VAS score change=-6.6±25.5) after imaging when pre-imaging confidence was moderate to high. Interestingly, a proportion of clinicians with the highest confidence levels became less certain about their diagnosis following imaging results. When asked directly, 96% of clinicians stated that the imaging contributed to the diagnostic process. CONCLUSIONS: In a mixed clinical cognitive impairment cohort, perfusion SPECT is valued by referring clinicians and contributes to diagnostic decision making. Imaging is of particular value when diagnostic confidence is low prior to imaging.

Computer simulation of dementia care demand heterogeneity using hybrid simulation methods: improving population-level modelling with individual patient decline trajectories.

OBJECTIVES: The aim of the study was to model dementia prevalence and outcomes within an ageing population using a novel hybrid simulation model that simultaneously takes population-level and patient-level perspectives to better inform dementia care service planning, taking into account severity progression variability. STUDY DESIGN: This is a simulation study. METHODS: We developed a hybrid computer simulation combining different methods to best represent population and individual dementia dynamics. Individual patient outcomes are aggregated into three progression rate types to report the effects of severity progression variability and intervention benefits. RESULTS: Fast progression of dementia severity is associated with higher annual care cost and short overall survival duration. Those patients are more likely to develop moderate to severe symptoms more quickly, highlighting a need for more urgent provision of appropriate care services. Slower severity progression is associated with lower annual care costs, but longer survival requires higher overall financial provision. Although lifestyle interventions reduce overall care costs, treatment and lifestyle intervention benefits are modest at the population level. CONCLUSIONS: Individual variation of dementia decline is an important factor to include in planning adequate levels of care services and to ensure timely and appropriate service availability. Hybrid simulation models provide useful insights at the population and individual level, supporting effective decision-making.

A case of recurrent swimming-induced pulmonary edema in a triathlete: the need for awareness.

This report discusses a rare case of a 55-year-old female triathlete who developed recurrent episodes of swimming-induced pulmonary edema (SIPE). She had two hospital admissions with pulmonary edema after developing breathlessness while swimming, including a near-drowning experience in an open water swim. With increasing popularity of triathlon and open water sports, this case highlights the importance of a greater awareness of SIPE among health professionals, event organizers, and athletes. This report explores the previous reported cases in triathletes and those who have suffered recurrent episodes. It is paramount that an accurate diagnosis is made as these individuals may be at an increased risk of future life-threatening episodes.

Negative schizophrenic symptoms and the frontal lobe syndrome: one and the same?

The negative symptoms of schizophrenia have been considered to be a psychiatric form of the frontal lobe syndrome. However, no studies have compared these two disorders at the clinical level. In this study, 12 negative symptom schizophrenic patients and 11 patients with behavioural variant frontotemporal dementia (bv-FTD) were rated for negative symptoms and for occurrence of frontal lobe behaviours in everyday life. They were also rated for speech disorder and were given a series of executive tests. Both patient groups showed positive ratings on negative symptoms and frontal lobe behaviours in daily life; however, the schizophrenic patients had higher negative symptom scores and the bv-FTD patients had higher carer ratings on frontal behaviours in daily life. Both groups were impaired on the executive tests, but the bv-FTD patients showed significantly greater impairment on verbal fluency and a test requiring inhibition of prepotent responses. A minority of the bv-FTD patients unexpectedly showed speech abnormalities typically associated with schizophrenia. The findings indicate that the negative syndrome in schizophrenia and the frontal lobe syndrome resemble each other clinically in important respects. Some of the differences may be attributable to the additional presence of disinhibition in the frontal lobe syndrome.

Understanding social dysfunction in the behavioural variant of frontotemporal dementia: the role of emotion and sarcasm processing.

Social interaction is profoundly affected in the behavioural form of frontotemporal dementia (bvFTD) yet there are few means of objectively assessing this. Diagnosis of bvFTD is based on informant report, however a number of individuals with a clinical profile consistent with the disease have no imaging abnormality and seem to remain stable, with doubt about the presence of underlying neurodegenerative pathology. We aimed to quantify aspects of the behavioural disorder and link it to the underlying level of atrophy in socially relevant brain regions. We tested individuals with either bvFTD (N = 26) or Alzheimer's disease (N = 9) and 16 controls using The Awareness of Social Inference Test (TASIT) to assess their ability to identify emotion and sarcasm in video vignettes. A subset of bvFTD patients (N = 21) and controls (N = 12) were scanned using MRI within 6 months of assessment. There was marked impairment in the ability of bvFTD patients whose scans showed abnormalities to recognize sarcastic, but not sincere statements. Their capacity to interpret negative emotion was also impaired, and this appeared to be a major factor underlying the deficit in sarcasm recognition. Clinically diagnosed bvFTD patients whose scans were normal, Alzheimer's disease patients and controls had no difficulty in appreciating both types of statement. In a multivariate imaging analysis it was shown that the sarcasm (and emotion recognition) deficit was dependent on a circuit involving the lateral orbitofrontal cortex, insula, amygdala and temporal pole, particularly on the right. Performance on a more global test of cognitive function, the Addenbrooke's Cognitive Examination did not have a unique association with these regions. The TASIT is an objective test of social dysfunction in bvFTD which indexes the frontotemporal volume loss in bvFTD patients and provides an objective measure for separating behavioural patients who are likely to decline from those who may remain stable. These results provide additional evidence for the role of the orbitofrontal cortex and related structures in the processing of socially relevant signals, particularly those where negative emotion recognition is important.

Combined magnetic resonance imaging and positron emission tomography brain imaging in behavioural variant frontotemporal degeneration: refining the clinical phenotype.

In patients with the behavioural variant of frontotemporal dementia, prognosis is often surprisingly good when there is normal structural imaging at presentation. Imaging abnormalities are not, however, mandatory for diagnosis, which in the absence of suitable biomarkers, remains entirely clinical. We aimed to test whether cases with normal structural imaging have hypometabolism suggestive of underlying neurodegeneration, or whether it is likely that such patients are false positive diagnoses of behavioural variant frontotemporal dementia. Patients with this disease (n = 24) and age-matched controls (n = 12) underwent both magnetic resonance imaging (MRI) and quantitative fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning, together with clinical and behavioural assessments. Regions of interest were used to calculate metabolic rate in frontotemporal and control regions. Using a semi-quantitative visual rating scale, patients were divided into MRI-abnormal (n = 15) and MRI-normal groups (n = 9). There was definite frontotemporal hypometabolism in the MRI-abnormal group (particularly in the mesial and orbitofrontal regions) even after accounting for brain volume loss, whereas the MRI-normal group was similar to controls in all regions. In contrast, cognitive and behavioural indices did not separate the two behavioural variant frontotemporal dementia patient groups. The results suggest that the clinical syndrome of the behavioural variant of frontotemporal dementia may not be specific for a neurodegenerative disease, and we hypothesize the existence of a phenocopy. A number of alternative neuropsychiatric and developmental explanations are discussed. We advise caution in diagnosing the illness in patients without imaging abnormalities, and propose that imaging findings are included in criteria for diagnosis.

Patella dislocation: an online systematic video analysis of the mechanism of injury.

BACKGROUND: The mechanism of injury (MoI) for a patellar dislocation has not been fully established. The aim of this study was to use systematic video analysis to determine the MoI of a patella dislocation. METHODS: A systematic search was conducted of three video sharing websites and three popular search engines to identify videos demonstrating a patellar dislocation. Videos were reviewed by three surgeons trained in systematic video analysis, who commented on the position of the lower limb and the situation in which the injury occurred. The results were reviewed to build a consensus of the MoI for each video. Statistical analysis was conducted for interobserver agreement (p < 0.05). RESULTS: Initial search yielded 603 videos with 13 meeting the inclusion criteria. The injuries were sustained performing a sporting activity (n = 9) or whilst dancing (n = 4). The injury was predominantly sustained during a non-contact situation (n = 10). The most common mechanism was an unbalanced individual with a flexed hip sustaining a valgus force to their flexed knee with the tibia externally rotated. CONCLUSIONS: This study provides some insight into the MoI for a patellar dislocation and the findings may assist in developing injury prevention programmes and rehabilitation protocols as well as guiding future research.

When does the patella dislocate? A systematic review of biomechanical & kinematic studies.

BACKGROUND: Patellar dislocations are a significant injury with the potential for long term problems. Little work has been done on establishing the mechanism by which this injury occurs. OBJECTIVES: To determine the mechanism of injury of a patella dislocation based on the available published literature and compare them to already proposed theories. METHODS: A systematic review of the literature was conducted following searches performed on MEDLINE, EMBASE and ProQuest from the earliest year of indexing using the following search terms in any combination: "patella", "dislocation", "mechanism of injury", "anatomy", "biomechanical" and "risk factor". A broad inclusion criteria was used that included studies that looked at patellar dislocations and instability with respect to the patellofemoral joint (PFJ) kinematics or altered kinematics of the PFJ. Studies that did not address the kinematics or biomechanics of the PFJ were excluded. Studies were appraised based on their methodology using a combination of the Critical Appraisal Skills Programme tool and the Quality Appraisal for Cadaveric Studies. RESULTS: 113 studies were identified from a search of MEDLINE, EMBASE and ProQuest databases. Following application of our inclusion criteria, a total of 23 studies were included in our review. 18 of these studies were cadaveric biomechanical studies. The remaining studies were anatomical, imaging based, and a computer simulation based study. CONCLUSIONS: These biomechanical and kinematic studies provide some evidence that a dislocation is likely to occur during early knee flexion with external rotation of the tibia and contraction of the quadriceps. There is limited evidence to support other elements of proposed mechanisms of dislocation.

Can progressive and non-progressive behavioural variant frontotemporal dementia be distinguished at presentation?

BACKGROUND: Recent findings suggest that patients with behavioural variant frontotemporal dementia (bv-FTD) differ in their disease progression (progressive vs non-progressive patients). The current study investigates whether the two groups can be discriminated by their clinical features at first presentation. METHODS: Archival clinical data of the Early Onset Dementia Clinic, Cambridge, UK, were analysed for 71 patients with bv-FTD: 45 progressive and 26 non-progressive cases with more than 3 years of follow-up. RESULTS: The subgroups were largely indistinguishable on the basis of the presenting clinical features but could be distinguished on general cognitive (Addenbrooke's Cognitive Examination-revised) and selected supportive diagnostic features (distractibility, stereotypic speech, impaired activities of daily living (ADLs) and current depression). CONCLUSIONS: Progressive and non-progressive patients are difficult to differentiate on the basis of current clinical diagnostic criteria for FTD but a combination of general cognitive, executive dysfunction and impaired ADL measures appear to be the most promising discriminators.

Disrupted sleep and circadian patterns in frontotemporal dementia.

BACKGROUND: A study of the pattern of Sleep/Wake disturbance in frontotemporal dementia (FTD). METHODS: Sleep diaries and prolonged actigraphy were used to record the activity, sleep and wake of 13 patients with a clinical diagnosis of FTD. These were compared with diaries and actigraphy from normal age/sex matched controls and also to a population with probable Alzheimer's disease (AD). RESULTS: There was significant sleep/wake disturbance in FTD. This occurred throughout the course of the illness and the nature of the sleep disturbance was different to patients with AD. FTD subjects showed increased nocturnal activity and decreased morning activity compared with controls, suggesting possible phase delay. Sleep diary data confirmed decreased sleep efficiency and decreased total sleep in all FTD patients. CONCLUSIONS: We describe significant sleep disturbance in non-institutionalized patients with FTD and suggest that early sleep disturbance may help differentiate between FTD and AD.

Measuring younger onset dementia: A comprehensive literature search of the quantitative psychosocial research.

BACKGROUND: Research is beginning to demonstrate the unique psychosocial effects of young onset dementia. Theorising remains at an early stage and there has been little discussion about measurement and methodological issues. Our aim was to conduct a comprehensive literature search of the young onset dementia psychosocial research, and to identify the domains of experience measured with patients and caregivers. METHOD: We conducted a search of five electronic databases (Medline, CINAHL, PsycINFO, Embase, the Cochrane Library) using equivalent database controlled vocabulary terms. We supplemented this search by using free text searches within electronic databases, searching reference sections of salient papers, and using online search engines. We defined psychosocial as referring to patient and caregiver psychological, behavioural, and social functioning in the context of living with young onset dementia. RESULTS: We identified 72 published articles, 49 quantitative and 23 qualitative. The quantitative articles form the focus of the present review. We identified 10 domains of patient experience measured and 14 domains of caregiver experience. The patient domains measured most often were behaviour, cognition, functioning, and severity, and reflected a focus on symptoms and clinical features. Quality of Life (QoL) was the patient domain measured least often. The caregiver domains measured most often were mental health and burden, and reflected a focus on psychological well-being and coping. CONCLUSION: The scope of measurement is broader in caregivers than patients. QoL although under-researched may be a useful domain to measure in future research. Risk factors, measurement and methodological issues are discussed.

Validating the portal population of the United Kingdom Multiple Sclerosis Register.

The UK Multiple Sclerosis Register (UKMSR) is a large cohort study designed to capture 'real world' information about living with multiple sclerosis (MS) in the UK from diverse sources. The primary source of data is directly from people with Multiple Sclerosis (pwMS) captured by longitudinal questionnaires via an internet portal. This population's diagnosis of MS is self-reported and therefore unverified. The second data source is clinical data which is captured from MS Specialist Treatment centres across the UK. This includes a clinically confirmed diagnosis of MS (by Macdonald criteria) for consented patients. A proportion of the internet population have also been consented at their hospital making comparisons possible. This dataset is called the 'linked dataset'. The purpose of this paper is to examine the characteristics of the three datasets: the self-reported portal data, clinical data and linked data, in order to assess the validity of the self-reported portal data. The internet (n = 11,021) and clinical (n = 3,003) populations were studied for key shared characteristics. We found them to be closely matched for mean age at diagnosis (clinical = 37.39, portal = 39.28) and gender ratio (female %, portal = 73.1, clinical = 75.2). The Two Sample Kolmogorov-Smirnov test was for the continuous variables to examine is they were drawn from the same distribution. The null hypothesis was rejected only for age at diagnosis (D = 0.078, p < 0.01). The populations therefore, were drawn from different distributions, as there are more patients with relapsing disease in the clinical cohort. In all other analyses performed, the populations were shown to be drawn from the same distribution. Our analysis has shown that the UKMSR portal population is highly analogous to the entirely clinical (validated) population. This supports the validity of the self-reported diagnosis and therefore that the portal population can be utilised as a viable and valid cohort of people with Multiple Sclerosis for study.

'Too much of a coincidence': identical twins with exertional heatstroke in the same race.

This report discusses a unique case of monozygotic male twins who both collapsed with exertional heat stroke (EHS) during the same marathon in relatively cool conditions. The twins were official race pacers in a popular city marathon held in the early spring in the UK. Both recovered uneventfully due to the prompt recognition of EHS and use of aggressive cooling measures, which prevented life-threatening complications. The case illustrates that EHS is a complex illness with a possible genetic predisposition, which can occur among runners even in cooler conditions. This link is explored together with the influence of their role as race pacers and the additional backpack worn in the development of EHS.

Lobar atrophy in frontotemporal dementia: diagnostic and prognostic implications.

We review the practical importance of lobar atrophy in frontotemporal dementia (FTD), for diagnosis and prognosis. We discuss specific patterns of frontotemporal atrophy that denote clinical and pathological subtypes of FTD (e.g. semantic dementia). We also discuss the unsatisfactory clinical experience of interpreting MRI scans in individual FTD cases, especially the behavioural presentations (without aphasic or motor impairments). This issue is explored by examining the FTD phenocopy concept. Lobar atrophy emerges as a key observation in defining behavioural FTD patients whose symptoms are likely to progress. In a situation where objective clinical data are few, we highlight the importance of applying caution before diagnosing FTD is the absence of visible brain atrophy.

Movement disorder emergencies in childhood.

The literature on paediatric acute-onset movement disorders is scattered. In a prospective cohort of 52 children (21 male; age range 2mo-15y), the commonest were chorea, dystonia, tremor, myoclonus, and Parkinsonism in descending order of frequency. In this series of mainly previously well children with cryptogenic acute movement disorders, three groups were recognised: (1) Psychogenic disorders (n = 12), typically >10 years of age, more likely to be female and to have tremor and myoclonus (2) Inflammatory or autoimmune disorders (n = 22), including N-methyl-d-aspartate receptor encephalitis, opsoclonus-myoclonus, Sydenham chorea, systemic lupus erythematosus, acute necrotizing encephalopathy (which may be autosomal dominant), and other encephalitides and (3) Non-inflammatory disorders (n = 18), including drug-induced movement disorder, post-pump chorea, metabolic, e.g. glutaric aciduria, and vascular disease, e.g. moyamoya. Other important non-inflammatory movement disorders, typically seen in symptomatic children with underlying aetiologies such as trauma, severe cerebral palsy, epileptic encephalopathy, Down syndrome and Rett syndrome, include dystonic posturing secondary to gastro-oesophageal reflux (Sandifer syndrome) and Paroxysmal Autonomic Instability with Dystonia (PAID) or autonomic 'storming'. Status dystonicus may present in children with known extrapyramidal disorders, such as cerebral palsy or during changes in management e.g. introduction or withdrawal of neuroleptic drugs or failure of intrathecal baclofen infusion; the main risk in terms of mortality is renal failure from rhabdomyolysis. Although the evidence base is weak, as many of the inflammatory/autoimmune conditions are treatable with steroids, immunoglobulin, plasmapheresis, or cyclophosphamide, it is important to make an early diagnosis where possible. Outcome in survivors is variable. Using illustrative case histories, this review draws attention to the practical difficulties in diagnosis and management of this important group of patients.

Sensitivity of current criteria for the diagnosis of behavioral variant frontotemporal dementia.

BACKGROUND: Diagnosis of behavioral variant frontotemporal dementia (bvFTD) relies on criteria that are constraining and potentially ambiguous. Some features are open to clinical interpretation and their prevalence unknown. This study investigated the sensitivity of current diagnostic criteria in a large group of patients with bvFTD. METHODS: Forty-five patients with clear evidence of bvFTD as judged by progressive clinical decline (>3 years) with marked frontal features and significant frontal brain atrophy on brain MRI were included. Thirty-two have died; pathologic confirmation of frontotemporal lobar degeneration was found in all 18 coming to autopsy. We established the prevalence of core and supportive diagnostic features at presentation and with disease progression. RESULTS: Only 25/45 patients (56%) showed all five core features necessary for a diagnosis of bvFTD at initial presentation and 33/45 (73%) as their disease progressed. Two core features, emotional blunting and loss of insight, were never observed in 25% and 13% of cases. Executive dysfunction, hyperorality, mental inflexibility, and distractibility were the only supportive features present in >50% of cases at initial presentation. Although not a diagnostic feature, impaired activities of daily living was present in 33/45 patients (73%). CONCLUSIONS: Strict application of the criteria misses a significant proportion of patients. Many supportive features have low prevalence and are clinically not useful. Revision of the criteria to include level of certainty (definite, probable, possible) dependent on the number of features present and the presence of ancillary information (e.g., brain atrophy, neuropsychological abnormalities, impaired activities of daily living) is encouraged.

Measuring progression in frontotemporal dementia: implications for therapeutic interventions.

BACKGROUND: There is a need for instruments which can measure progression of disease in frontotemporal dementia (FTD), particularly with respect to the assessment of potential therapeutic agents. METHODS: The Cambridge Early Onset Dementia Clinic database was reviewed for all prospectively enrolled cases of FTD with documented scores on the Mini-Mental State Examination (MMSE) or Addenbrooke's Cognitive Examination (ACE) on at least two occasions. We identified 50 cases fulfilling these criteria: pathologic confirmation was present in 11 of 16 patients who had died, 12 of the remainder had imaging abnormalities on their initial scans, and 22 had structural scans no different from controls. We compared these groups to a cohort with early AD (n = 25) and healthy controls (n = 10). RESULTS: There was clear cognitive decline (measured by the MMSE and ACE) in patients who had died, and those with documented atrophy on initial MRI scan. In contrast, patients with FTD with normal scans showed no change in cognitive scores over a much longer interval, and serial ACE measurements paralleled those of controls. Power calculations showed that the inclusion of these patients with FTD would significantly increase the number of cases needed in any therapeutic trial. CONCLUSION: Addenbrooke's Cognitive Examination is a simple monitoring tool which can detect progression of disease in frontotemporal dementia over a 1- to 2-year interval without the need for serial imaging. We estimated that a clinical trial that enrolled subjects with abnormal MR scans would require 135 subjects per group to detect a small effect, and 35 for a medium effect.

Behavioural variant frontotemporal dementia: not all it seems?

BACKGROUND: The diagnosis of the behavioural variant of frontotemporal dementia (bvFTD) can be challenging. At present there is a paucity of prospective work addressing the specificity of current diagnostic criteria for bvFTD with respect to long-term outcome (i.e., false positives versus true positives). METHODS: Here we report two individuals who met current clinical criteria for bvFTD and who underwent detailed long-term clinical and neuropsychological follow-up. In addition, both had serial volumetric MRI and functional metabolic (FDG-PET) imaging separated by 5 years. RESULTS: One case had a slow clinical decline as well as both progressive atrophy and hypometabolism in a frontotemporal distribution, consistent with a neurodegenerative FTD syndrome. However, the second developed neither atrophy nor hypometabolism and remained clinically stable, a decade from symptom onset. CONCLUSION: We propose that these cases illustrate that while there may be a slow evolution in bvFTD, it is possible that some cases who meet current criteria may not have a neurodegenerative syndrome. If correct, this hypothesis has important implications for the current diagnostic criteria. A potential hierarchy for diagnostic certainty in bvFTD is suggested.