Peripheral vascular responses to acetylcholine as a predictive tool for response to cholinesterase inhibitors in Alzheimer's disease.

BACKGROUND: Cholinesterase inhibitors remain the first line therapy for people with mild to moderate Alzheimer's disease (AD). Response is modest and difficult to predict from pre-treatment characteristics. We hypothesise that skin vascular response to iontophoresis of acetylcholine, which is partly determined by the level of cholinesterase activity, may be a pre-treatment measure that could predict response to therapy. METHODS: Twenty-four people with probable AD underwent iontophoresis of acetylcholine to the volar surface of the forearm skin prior to treatment with a cholinesterase inhibitor. The peak skin vascular response and the resolution to baseline levels were measured using laser Doppler perfusion imaging. Response to treatment was assessed after 6 months using criteria from the National Institute for Health and Care Excellence (NICE) and iontophoresis with acetylcholine was repeated. Blindness between clinical and laboratory assessments was maintained. RESULTS: Fourteen out of twenty-four people responded to treatment using NICE criteria. By comparison to non-responders, responders to treatment had a faster resolution to baseline from acetylcholine-induced vasodilation prior to treatment, which slowed with treatment. In this pilot study there was a high level of accuracy in the classification of response using this variable. No baseline cognitive or functional measures discriminated end-point responders from non-responders. CONCLUSION: Cholinesterase inhibitors are well tolerated but the number of people with adverse effects would be reduced if it was possible to predict response. The role of vasodilator response to acetylcholine and recovery as a potential biomarker for efficacy of treatment should now be evaluated and may possibly be of relevance in stratifying samples for interventional studies in AD and other forms of dementia. We feel that a more definitive study is now justified.

The Effect of Understanding Issues of Personal Finance on the Well-being of Physicians in Training.

BACKGROUND: This study assessed trends in personal financial issues among physical medicine and rehabilitation resident physicians and their impact on resident well-being. METHODS: A 25-question cross-sectional survey was sent to 18 physical medicine and rehabilitation residents. RESULTS: A total of 17 residents completed the survey (94% response rate), with 82% (14 of 17) endorsing personal finances as a contributor to their personal health. Residents also endorsed minimal previous financial education and an interest in more formal education on related topics. DISCUSSION: This study revealed personal financial issues are a factor in resident well-being and garner high levels of interest. Despite this, residents have received little financial education. These results have motivated us to address this deficit in our education program.

Sport-Related Concussion Reporting and State Legislative Effects.

OBJECTIVE: To investigate concussion rates and reporting frequencies in high school and collegiate athletes in 2013, compare results to those obtained from 1999 to 2002, and examine to what extent the 2012 Wisconsin state concussion law affected reporting in 2013. DESIGN: Retrospective 2013 survey compared with prior survey. SETTING: High schools and colleges in the Milwaukee, Wisconsin, area. PARTICIPANTS: Athletes (N = 784) from multiple sports were surveyed in 2013. Football players (N = 1532) from 1999 to 2002 completed the same measure. MAIN OUTCOME MEASURES: Both surveys assessed concussion history, concussion incidence during the current season, whether incident concussions were reported, who concussions were reported to, and reasons for not reporting. The 2013 survey also assessed awareness of the Wisconsin state law and its effect on reporting. RESULTS: Rates of concussion in the surveyed season were comparable to previous findings from 1999 to 2002 (16.6% vs 15.3%, P = 0.558). Notably, athletes were significantly more likely to report their concussions in 2013 (70.6% vs 47.3% previously, P = 0.011). Among high school athletes surveyed, 59.5% were aware of the Wisconsin state law, with 55.1% stating it would make them more likely to report a concussion. CONCLUSIONS: Rates of concussion for 1 sport season have not changed significantly over the past 14 years. The percentage of concussions that are reported to someone has increased significantly. Awareness of the Wisconsin state law does not fully account for the increase in concussion reporting. CLINICAL RELEVANCE: Given the finite amount of knowledge regarding the influence of concussion-related cultural and legal changes, these findings will help to inform clinicians of the current concussion milieu from the perspective of athletes. It will inform practitioners involved in concussion management to what extent athletes are aware of and report concussions.

Prediction of general hospital admission in people with dementia: cohort study.

BACKGROUND: People with dementia are extremely vulnerable in hospital and unscheduled admissions should be avoided if possible. AIMS: To identify any predictors of general hospital admission in people with dementia in a well-characterised national prospective cohort study. METHOD: A cohort of 730 persons with dementia was drawn from the Scottish Dementia Research Interest Register (47.8% female; mean age 76.3 years, s.d. = 8.2, range 50-94), with a mean follow-up period of 1.2 years. RESULTS: In the age- and gender-adjusted multivariable model (n = 681; 251 admitted), Neuropsychiatric Inventory score (hazard ratio per s.d. disadvantage 1.21, 95% CI 1.08-1.36) was identified as an independent predictor of admission to hospital. CONCLUSIONS: Neuropsychiatric symptoms in dementia, measured using the Neuropsychiatric Inventory, predict non-psychiatric hospital admission of people with dementia. Further studies are merited to test whether interventions to reduce such symptoms might reduce unscheduled admissions to acute hospitals.

Does the Addenbrooke's Cognitive Examination-revised add to the Mini-Mental State Examination in established Alzheimer disease? Results from a national dementia research register.

OBJECTIVE: To evaluate how much the Addenbrooke's Cognitive Examination-revised (ACE-R) improves the estimate of cognitive ability from the Mini-Mental State Examination (MMSE) in people with Alzheimer disease (AD). METHODS: We examined itemized data in people with AD who were on the Scottish Dementia Research Interest Register drawn from eight centres across Scotland, covering 75% of the Scottish population. ACE-R items that comprise the MMSE and those that did not (non-MMSE items) were summed separately. We residualized MMSE total on non-MMSE total and vice versa to derive a measure of the variance unique to each. RESULTS: Five hundred and one (258 male, 243 female) participants, mean age 75.7 (range 52-94) years were on the register, of whom 329 (160 men, 169 women) had AD. Of those with AD, 309 had a mean MMSE of 20.5 and mean ACE-R of 57.5 measured with Pearson r = 0.92 between MMSE and ACE-R totals, and the regression equation ACE-R score = 3.0 × MMSE - 4.1. The unique non-MMSE items score correlated with ACE-R total r = 0.40 (16% of ACE-R variance). CONCLUSIONS: The ACE-R and MMSE total scores are highly correlated. In this clinical sample of people with established AD, for an MMSE score of 24, the predicted ACE-R score was 67.9 with 95% confidence intervals of 61.6-75.4. The extra non-MMSE ACE-R items improve estimates of cognitive ability by 16%.

What motivates patients and carers to participate in dementia studies?

AIM: The aim of this study was to explore what motivates people to participate in dementia research. METHOD: Three focus groups, attended by carers and people with dementia who had already volunteered to take part in dementia research, were used to explore motivation. Their thoughts and feelings about brain tissue donation were also explored. An adaptation of the participation chain model was used. A fourth focus group was given a supplementary questionnaire examining use of resources. Focus group content was analysed using a content analysis approach to identify themes. FINDINGS: Individualistic motivations included increased confidence and a chance to have a say. Collectivistic motivations included 'helping through being part of something bigger'. Mobilisation (catalysing) issues included a desire for change, and 'being asked'. In response to the questionnaire participants identified that they would have taken part regardless of any tangible benefits, with all saying that they would not have been put off by any of the costs. CONCLUSION: Participants in these focus groups were keen to be involved in dementia research and discounted any potential costs to themselves. They highlighted that being asked was an important factor in engaging them in dementia research.

Retinal vascular measures from diabetes retinal screening photographs and risk of incident dementia in type 2 diabetes: A GoDARTS study.

Objective: Patients with diabetes have an increased risk of dementia. Improved prediction of dementia is an important goal in developing future prevention strategies. Diabetic retinopathy screening (DRS) photographs may be a convenient source of imaging biomarkers of brain health. We therefore investigated the association of retinal vascular measures (RVMs) from DRS photographs in patients with type 2 diabetes with dementia risk. Research Design and Methods: RVMs were obtained from 6,111 patients in the GoDARTS bioresource (635 incident cases) using VAMPIRE software. Their association, independent of Apo E4 genotype and clinical parameters, was determined for incident all cause dementia (ACD) and separately Alzheimer's disease (AD) and vascular dementia (VD). We used Cox's proportional hazards with competing risk of death without dementia. The potential value of RVMs to increase the accuracy of risk prediction was evaluated. Results: Increased retinal arteriolar fractal dimension associated with increased risk of ACD (csHR 1.17; 1.08-1.26) and AD (HR 1.33; 1.16-1.52), whereas increased venular fractal dimension (FDV) was associated with reduced risk of AD (csHR 0.85; 0.74-0.96). Conversely, FDV was associated with increased risk of VD (csHR 1.22; 1.07-1.40). Wider arteriolar calibre was associated with a reduced risk of ACD (csHR 0.9; 0.83-0.98) and wider venular calibre was associated with a reduced risk of AD (csHR 0.87; 0.78-0.97). Accounting for competing risk did not substantially alter these findings. RVMs significantly increased the accuracy of prediction. Conclusions: Conventional DRS photographs could enhance stratifying patients with diabetes at increased risk of dementia facilitating the development of future prevention strategies.

An international perspective on advanced neuroimaging: cometh the hour or ivory tower?

Over the past five to ten years, neuroimaging capability for neurodegenerative diseases has made remarkable progress. However, debate remains as to the true clinical utility of these advanced and costly investigations. Not only is the place of these tests in diagnostic algorithms unclear, but the access to them varies both within and between countries. We sought to gather informed opinion from recognized leaders in the field who can combine both an academic and a clinical perspective on the use of neuroimaging in their own countries. Opinion is presented from Scotland, Argentina, the Czech Republic, France, the USA and Australia. The emerging consensus was one of ongoing caution. While in most countries there was a sense that the use of more advanced imaging techniques was growing, their hour has not yet cometh. However, these techniques, rather than falling from the Ivory Tower, should descend slowly step by step onto fertile and receptive clinics from where better clinical guidelines will emerge.

Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective.

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease-modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of Phase II, Phase II/III and Phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15 000 people with amyotrophic lateral sclerosis. About 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis.

Fifteen year comparison of antipsychotic use in people with dementia within hospital and nursing home settings: sequential cross-sectional study.

OBJECTIVE: The use of antipsychotics to treat people with behavioural and psychological symptoms associated with dementia is controversial, especially in long-stay settings. We assessed the relationship between behaviour, function and antipsychotic use in people with dementia in a long-stay psychiatric unit and designated elderly mentally ill (EMI) nursing homes over a 15-year period. METHOD: Sequential cross-sectional studies assessing twelve behaviours and seven measures of function for each patient. Antipsychotic and antidepressant use was obtained from current prescription records. RESULTS: Regular antipsychotic use in hospital fell between 1990 and 1998. In 1998 use in nursing homes was significantly greater than in hospital, and increased between 1998 and 2005. Noisiness/verbal aggression (NVA) was the only behaviour more commonly associated with regular antipsychotic use over that timescale. Those with low levels of core symptoms (p = 0.021) and high dependency patients (p = 0.001) were more likely to be receiving regular antipsychotics in nursing homes than in hospital. Depression was not treated well even when identified. CONCLUSION: Compared to a long-stay hospital setting, antipsychotic drug use for people with dementia in nursing homes has risen and become less systematic. This cannot be explained by increasing core behaviour symptoms or differences in physical dependency.

Meeting Increased Demand for Mosquito Adulticides Containing the Active Ingredient Naled Following Hurricanes and Tropical Storms.

The occurrence of tropical storms and hurricanes is a certainty in the Atlantic Basin each year. Many of these never make landfall. Those that do can range in intensity from a weak tropical depression to a very destructive Category 5 hurricane. These storms often produce large amounts of rainfall and flooding, resulting in increases in the mosquito populations in the affected areas. In order to deal with this problem, aerial applications of insecticides over wide areas can provide relief to the impacted area, assisting in the recovery efforts. Meeting the demand for these sudden and large increases in the volume of the insecticide most commonly used in aerial applications requires great coordination, communication, and commitment. We describe the diverse entities involved in the manufacture, distribution, and use of the product and how this increase in need is recognized, managed, and satisfied in a compressed period of time.

Investigating the Relationship Between Type 2 Diabetes and Dementia Using Electronic Medical Records in the GoDARTS Bioresource.

OBJECTIVE: To investigate the impact of type 2 diabetes on incidence of major dementia subtypes, Alzheimer and vascular dementia, using electronic medical records (EMR) in the GoDARTS bioresource. RESEARCH DESIGN AND METHODS: GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) comprises a large case-control study of type 2 diabetes with longitudinal follow-up in EMR. Dementia case subjects after recruitment were passively identified in the EMR, and using a combination of case note review, an Alzheimer-specific weighted genetic risk score (wGRS), and APOE4 genotype, we validated major dementia subtypes. We undertook a retrospective matched cohort study to determine the risk of type 2 diabetes status for incident dementia accounting for competing risk of death. RESULTS: Type 2 diabetes status was associated with a significant risk of any dementia (cause-specific hazard ratio [csHR] 1.46, 95% CI 1.31-1.64), which was attenuated, but still significant, when competing risk of death was accounted for (subdistribution [sd]HR 1.26, 95% CI 1.13-1.41). The accuracy of EMR-defined cases of Alzheimer or vascular dementia was high-positive predictive value (PPV) 86.4% and PPV 72.8%, respectively-and wGRS significantly predicted Alzheimer dementia (HR 1.23, 95% CI 1.12-1.34) but not vascular dementia (HR 1.02, 95% CI 0.91-1.15). Conversely, type 2 diabetes was strongly associated with vascular dementia (csHR 2.47, 95% C 1.92-3.18) but not Alzheimer dementia, particularly after competing risk of death was accounted for (sdHR 1.02, 95% CI 0.87-1.18). CONCLUSIONS: Our study indicates that type 2 diabetes is associated with an increased risk of vascular dementia but not with an increased risk of Alzheimer dementia and highlights the potential value of bioresources linked to EMR to study dementia.

Aerial ULV control of Aedes aegypti with naled (Dibrom) inside simulated rural village and urban cryptic habitats.

We conducted aerial fixed wing ultra low volume (ULV) spray trials with naled to investigate penetration of exposed and simulated cryptic habitat within opened buildings, partially sealed buildings, and outdoor locations targeting sentinel adult Aedes aegypti mosquitoes in north central Florida. Mortality was observed in open and closed buildings and outdoors, even in mosquitoes placed in cryptic habitats. Observations on the impact of building type, mosquito exposure method such as placement in cryptic habitat, and spray nozzle size on mosquito mortality are described and analyzed.

Genetic education in dementia care.

AIM: To demonstrate the benefits of collecting family history systematically to enhance the care provided to families living with dementia. In addition, to identify the contribution nurses can make in responding to relatives' concerns about dementia and its risk factors. METHOD: An individual case study was derived from a larger observational study of the psycho-educational needs of families affected by dementia. This case study presents extracts from one anonymised interview with an adult son whose father has dementia. FINDINGS: The family of the patient with dementia did not feel they had a positive experience of care delivery. Although they had a high level of knowledge and personal experience of dementia, their beliefs and concerns appear to have been overlooked by healthcare staff. This may have led to a delay in the diagnosis of dementia and missed opportunities for earlier treatment. CONCLUSION: Healthcare staff should consider the concerns expressed by people with dementia and their families. Knowledge of the risk factors for dementia and risk-reduction strategies can improve the care nurses provide. This should include an increased awareness of the complex interaction between genes, environment and lifestyle.

A randomised controlled trial of calcium channel blockade (CCB) with Amlodipine For the treatment oF subcortical ischaEmic vasCular demenTia (AFFECT): study protocol.

BACKGROUND: Vascular dementia is the second most common cause of dementia affecting over seven million people worldwide, yet there are no licensed treatments. There is an urgent need for a clinical trial in this patient group. Subcortical ischaemic vascular dementia is the most common variant of vascular dementia. This randomised trial will investigate whether use of calcium channel blockade with amlodipine, a commonly used agent, can provide the first evidence-based pharmacological treatment for subcortical ischaemic vascular dementia. METHODS/DESIGN: This is a randomised controlled trial of calcium channel blockade with Amlodipine For the treatment oF subcortical ischaEmic vasCular demenTia (AFFECT) to test the hypothesis that treatment with amlodipine can improve outcomes for these patients in a phase IIb, multi-centre, double-blind, placebo-controlled randomised trial. The primary outcome is the change from baseline to 12 months in the Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog). Secondary outcomes include cognitive function, executive function, clinical global impression of change, change in blood pressure, quantitative evaluation of lesion accrual based on magnetic resonance imaging (MRI), health-related quality of life, activities of daily living, non-cognitive dementia symptoms, care-giver burden and care-giver health-related quality of life, cost-effectiveness and institutionalisation. A total of 588 patients will be randomised in a 1:1 ratio to either amlodipine or placebo, recruited from sites across the UK and enrolled in the trial for 104 weeks. DISCUSSION: There are no treatments licensed for vascular dementia. The most common subtype is subcortical ischaemic vascular dementia (SIVD). This study is designed to investigate whether amlodipine can produce benefits compared to placebo in established SIVD. It is estimated that the numbers of people with VaD and SIVD will increase globally in the future and the results of this study should inform important treatment decisions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN31208535 . Registered on 7 March 2014.

Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review.

INTRODUCTION: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia. METHODS: The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review. RESULTS: In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer's disease and healthy controls. CONCLUSION: IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.

Association of a salivary acetylcholinesterase with Alzheimer's disease and response to cholinesterase inhibitors.

OBJECTIVES: A decrease in cholinergic activity is a key event in the biochemistry of Alzheimer's disease (AD). The aim of the study was to investigate the expression levels of markers of cholinergic function in saliva, which is a readily accessible body fluid that can be obtained from subjects with minimal distress. DESIGN AND METHODS: Salivary samples were obtained from people with NINCDS-ARDRA "probable" Alzheimer's disease and age- and sex-matched controls. Salivary acetylcholinesterase enzyme (AChE) activity was determined colorometrically. RESULTS: Robust AChE catalytic activity was detected in the saliva samples that was stable for up to 6 h at room temperature following the provision of the salivary sample. The activity of the enzyme was significantly lower in people with AD than in age-matched controls. In addition, there were significant differences in activity between those who responded to acetylcholinesterase inhibitor (AChE-I) therapy and those who did not. CONCLUSIONS: Salivary enzyme activity may therefore prove to be a useful marker of central cholinergic activity.