Simon M. Bell

How the UK describes functional memory symptoms

Functional neurological symptoms are thought to be caused by dysfunction in cognitive processing, which leads to physical symptoms without underlying brain pathology. These functional symptoms are commonly seen in neurology and psychiatric clinics, and examples include non-epileptic attacks and functional tremor. Some memory complaints may also be recognized as a functional symptom. The 2015 Royal College of Psychiatrists audit found UK memory clinics assessed, on average, 30.9% more patients in 2014 than in 2013. This has been associated with an increase in the number of people referred to memory clinics without neurodegenerative conditions. Patients who seek help for concerns about memory represent a heterogeneous cohort, but in many cases, they do not have dementia. Functional memory complaints are included in this non-neurodegenerative group. As functional memory symptoms appear to be increasing in UK memory clinics, we surveyed neurologists and psychiatrists working in these settings. An email survey was sent to 55 Neurologists running memory clinics in the UK by the Specialist Interest Group of the Association of British Neurologists on 22nd July 2013. A similar online survey, with additional questions about the treatment of functional neurological symptoms, was distributed to the Royal College of Psychiatrists Old Age Faculty mailing list on 23 April 2015. The list represents 1583 consultant old age psychiatrists working in the UK in a variety of settings, including 222 memory assessment services. Both neurologists and psychiatrists were given 3 months to respond. Eleven (of 55) neurology-led memory clinics and 33 psychiatrists responded. Data from psychiatrists represented 32 memory clinics or memory services within older adult community mental health teams. The mean estimated prevalence of dementia was 50.6% in people attending the neurology-led memory clinics and 69.0% in the psychiatry-led clinics. All of the neurology-led survey respondents and nearly two-thirds (65.6%) of the psychiatry respondents recognized functional memory symptoms, which was defined in our surveys as: ‘a patient presenting with a memory complaint, but no evidence of organic dementia or major psychiatric illness on neuropsychological or radiological investigation’. Although the majority of doctors recognized functional memory disorders (FMD) as a condition they see, there was no consensus on terminology used to describe this syndrome. Table 1 shows the terms used. Of the psychiatrists surveyed, 73.1% discharged patients with FMD to primary care. Of those who treated patients with FMD, there was no agreement on what was appropriate. Treatments included doing nothing, reassurance, psychology assessment, community mental health team referral, or commencement of selective serotonin reuptake inhibitors. The lack of agreement on terminology may affect treatment. Giving patients a clear label for a condition can help understanding and facilitate access to peer support. Current terms used to describe FMD vary dramatically, with some seeking to normalize the symptoms and others trying to explain the cause. It is likely that more than one type of FMD exists. However, multiple diagnostic categories may not demonstrate clinical utility. Comparing FMD to nonepileptic attacks illustrates that a label is important, and how symptoms are described and explained can affect patient engagement with therapy. A questionnaire study found ‘functional’ was more acceptable to patients than terms such as ‘pseuodseizures’ and ‘symptoms in the mind’. As diagnostic memory clinics are primarily concerned with the diagnosis and treatment of dementia, it may not be appropriate or feasible for FMD to be managed in this setting, and most patients will be discharged to primary care. Treatment for FMD is not well

QEEG CAN DISTINGUISH PATIENTS WITH AD AND VOLUNTEERS

Introduction Quantitative Electroencephalography (qEEG) has been shown to distinguish AD patients from healthy controls (HC) at a group but not at an individual level. A novel qEEG data analysis method created at the University of Sheffield can measure linear and non-linear levels of brain synchronisation in the time domain. Methods Patients with AD and HV had resting state EEGs. The standard 10–20 international system of EEG electrode placement was used. All patients had MRI and detailed neuropsychology as part of the European VPH-DARE@IT project. Custom made software (Error Reduction Ratio-causality (ERR-causality) analysed average strength of linear and non-linear synchronization in bicentroparietal region. Results 10 HC and 10 AD EEGs were included. Mean ages were 58.1 (AD) versus 62.2 y (HV). Mean mini-mental state examinations were 17.5 (AD) and 28.50 (HV). The ratio of bi-centroparietal synchronisation between eyes open & eyes close (EO/EC) showed a striking difference between the two groups (AD ratio 0.814 versus HC ratio 0.282, p=0.0006). Conclusions These results suggest that patients with AD have higher levels of EO bi-centroparietal synchronisation & in particular the ratio between EO/EC synchronisation has potential to be used as a non-invasive and inexpensive biomarker or diagnostic tool for AD.

Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with either Sporadic or Familial Alzheimer's Disease

Alzheimers disease (AD) is the leading cause of dementia worldwide. Mitochondrial abnormalities have been identified in many cell types in AD, with deficits preceding the development of the classical pathological aggregations. Ursodeoxycholic acid (UDCA), a treatment for primary biliary cirrhosis, improves mitochondrial function in fibroblasts derived from Parkinsons disease patients as well as several animal models of AD and Parkinsons disease. In this paper, we investigated both mitochondrial function and morphology in fibroblasts from patients with both sporadic and familial AD. We show that both sporadic AD (sAD) and PSEN1 fibroblasts share the same impairment of mitochondrial membrane potential and alterations in mitochondrial morphology. Mitochondrial respiration, however, was decreased in sAD fibroblasts and increased in PSEN1 fibroblasts. Morphological changes seen in AD fibroblasts include reduced mitochondrial number and increased mitochondrial clustering around the cell nucleus as well as an increased number of long mitochondria. We show here for the first time in AD patient tissue that treatment with UDCA increases mitochondrial membrane potential and respiration as well as reducing the amount of long mitochondria in AD fibroblasts. In addition, we show reductions in dynamin-related protein 1 (Drp1) level, particularly the amount localized to mitochondria in both sAD and familial patient fibroblasts. Drp1 protein amount and localization were increased after UDCA treatment. The restorative effects of UDCA are abolished when Drp1 is knocked down. This paper highlights the potential use of UDCA as a treatment for neurodegenerative disease.

A Pilot Study Investigating a Novel Non-Linear Measure of Eyes Open versus Eyes Closed EEG Synchronization in People with Alzheimer’s Disease and Healthy Controls

Background: The incidence of Alzheimer disease (AD) is increasing with the ageing population. The development of low cost non-invasive diagnostic aids for AD is a research priority. This pilot study investigated whether an approach based on a novel dynamic quantitative parametric EEG method could detect abnormalities in people with AD. Methods: 20 patients with probable AD, 20 matched healthy controls (HC) and 4 patients with probable fronto temporal dementia (FTD) were included. All had detailed neuropsychology along with structural, resting state fMRI and EEG. EEG data were analyzed using the Error Reduction Ratio-causality (ERR-causality) test that can capture both linear and nonlinear interactions between different EEG recording areas. The 95% confidence intervals of EEG levels of bi-centroparietal synchronization were estimated for eyes open (EO) and eyes closed (EC) states. Results: In the EC state, AD patients and HC had very similar levels of bi-centro parietal synchronization; but in the EO resting state, patients with AD had significantly higher levels of synchronization (AD = 0.44; interquartile range (IQR) 0.41 vs. HC = 0.15; IQR 0.17, p < 0.0001). The EO/EC synchronization ratio, a measure of the dynamic changes between the two states, also showed significant differences between these two groups (AD ratio 0.78 versus HC ratio 0.37 p < 0.0001). EO synchronization was also significantly different between AD and FTD (FTD = 0.075; IQR 0.03, p < 0.0001). However, the EO/EC ratio was not informative in the FTD group due to very low levels of synchronization in both states (EO and EC). Conclusion: In this pilot work, resting state quantitative EEG shows significant differences between healthy controls and patients with AD. This approach has the potential to develop into a useful non-invasive and economical diagnostic aid in AD.

Patients who are not driving 6 weeks after transient ischaemic attack have higher levels of anxiety

Dear Editor, Transient ischaemic attack (TIA) is by definition a condition with no long-term consequences. Evidence is emerging that what we have considered to be a TIA in the past does have effects that can last for many weeks. We recently audited our highand low-risk TIA clinics, in particular investigating whether patients were being informed of the driving restrictions advised by the UK Driver and Vehicle Licensing Agency. We found that most people were informed of the driving regulations post TIA, but some patients had decided not to return to driving after 4 weeks. In total, 90 patients were interviewed during a 2month audit process. Of these, 57 patients (43 patients did not have a TIA) were asked questions about their driving status; 33 responded that they had driven before the TIA and 24 said they had not. After the TIA, 13 patients (39.4%; mean age: 66.3 years) did not return to driving. The level of anxiety in the TIA patients who did not return to driving was high at 6 weeks (Generalized Anxiety Disorder 7 mean: 5.42; 95% confidence interval: 1.86–8.98) compared to those who had returned to driving (mean age 73.4 years; Generalized Anxiety Disorder 7 mean: 1.45; 95% confidence interval: 0.6–2.3). The average Montreal Cognitive Assessment score was 2 points higher in the group that had not returned to driving (26 vs 24). These results suggest that although physical recovery post TIA may happen quickly, functional cognitive recovery can take longer than 24 h. The fact that nearly 40% of our patients did not return to driving is quite striking. Moreover, not driving can potentially lead to social isolation. The majority of patients that did not return to driving were anxious. Driving may be only one example of multiple aspects of a patient’s functional life that are affected after TIA. Anxiety is a psychological condition that is amenable to different treatments. Prior research has also shown lasting effects on cognition and mood after TIA. Mood disturbance can last for 12 months or longer, and cognitive disorders can last for many years. Although the rapid nature of TIA clinical assessment enables patients to be treated quickly, the diagnosis, management, and acceptance of psychological consequences of a TIA may not be fully realized by the patient or physician in this setting. Screening to detect anxiety and depression are likely to be required very early in TIA management, something that is currently not done routinely. As more evidence emerges that TIA may have long-term consequences, this may mean that followup should extend beyond 6 weeks. This will be a significant challenge to available resources and may require joint ventures between both stroke and primary health services, involving multidisciplinary teams.

Treatment of the unknown patient: insights from acute stroke

When an unidentified patient who cannot communicate presents with symptoms and signs suggesting an acute stroke, the decision to thrombolyse is a particular challenge. In a time-pressured environment, clinicians need clear thought processes for diagnosis and treatment. Ethical considerations, diagnosis, identity and previous history, contraindications, time of symptom onset (EDICT) can help decision-making in this situation.

MITOCHONDRIAL ABNORMALITIES ARE FOUND IN FIBROBLASTS FROM SPORADIC ALZHEIMER’S DISEASE PATIENTS: RECOVERY WITH URSODOXYCHOLIC ACID TREATMENT

50% declined assessments were due to participants taking holidays. 1 participant withdrew from the study, with 1 visit remaining. The AS questionnaire asked if participants would be willing to enter a similar study; all respondents answered ‘yes’. Participants indicated a high degree of acceptability on all measures, reporting their overall experience as ‘good’ or ‘excellent’. Conclusions: We found that our complex protocol could be effectively established across multiple sites and that trial participants were sufficiently committed throughout the study, despite taxing study demand. We gained vital feedback and experience from conducting this pilot study, which will be utilised in a full trial in a greater number of participants.

QUANTITATIVE EEG CAN IDENTIFY DIFFERENCE BETWEEN PATIENTS WITH ALZHEIMER'S DISEASE AND HEALTHY VOLUNTEERS ON AN INDIVIDUAL LEVEL

ate AD patients were administered a single IV dose of LY (0.1 mg/kg IV to 10 mg/kg IV) or placebo during the single ascending dose (SAD) phase, followed by a 12 week follow-up period. The same patients proceeded into the multiple-ascending dose (MAD) phase and were administered up to 4 additional monthly IV doses of LY (0.3 mg/kg IV to 10 mg/kg IV) or placebo, depending on the initial SAD cohort. Adverse events, vital signs, ECGs, clinical laboratories, and neurological exams were assessed throughout the study and for up to 84 days after last dose to characterize safety and tolerability. Results: 37 patients received LY and 12 received placebo in the SAD/MAD cohorts. The 49 subjects had a mean age of 74 yrs (68yrs) with 57% female and 43%male. 53% had a Clinical Dementia Rating (CDR)1⁄40.5; 43% had CDR1⁄41, and 4% had CDR1⁄42. Subjects had florbetapir PET scans at screening and 7 months after the first dose (233644 days from screening) for quantitation of change in cerebral amyloid burden. MRI assessments for amyloid related imaging abnormalities were performed at screening, four weeks after the single dose, and at the end of the multiple dose phase. PK and immunogenicity assessments were performed throughout the trial. Conclusions: Safety, pharmacokinetics (PK), and florbetapir PET after multiple dose administration of LY will be presented.