Population incidence and associated mortality of urinary tract infection in people living with dementia.

OBJECTIVES: Urinary tract infections (UTIs) frequently cause hospitalisation and death in people living with dementia (PLWD). We examine UTI incidence and associated mortality among PLWD relative to matched controls and people with diabetes and investigate whether delayed or withheld treatment further impacts mortality. METHODS: Data were extracted for n = 2,449,814 people aged ≥ 50 in Wales from 2000-2021, with groups matched by age, sex, and multimorbidity. Poisson regression was used to estimate incidences of UTI and mortality. Cox regression was used to study the effects of treatment timing. RESULTS: UTIs in dementia (HR=2.18, 95 %CI [1.88-2.53], p < .0) and diabetes (1.21[1.01-1.45], p = .035) were associated with high mortality, with the highest risk in individuals with diabetes and dementia (both) (2.83[2.40-3.34], p < .0) compared to matched individuals with neither dementia nor diabetes. 5.4 % of untreated PLWD died within 60 days of GP diagnosis-increasing to 5.9 % in PLWD with diabetes. CONCLUSIONS: Incidences of UTI and associated mortality are high in PLWD, especially in those with diabetes and dementia. Delayed treatment for UTI is further associated with high mortality.

Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer's Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments.

BACKGROUND: Guanfacine is a α2A adrenergic receptor agonist approved for treating attention deficit hyperactivity disorder (ADHD). It is thought to act via postsynaptic receptors in the prefrontal cortex, modulating executive functions including the regulation of attention. Attention is affected early in Alzheimer's disease (AD), and this may relate to pathological changes within the locus coeruleus, the main source of noradrenergic pathways within the brain. Given that cholinergic pathways, also involved in attention, are disrupted in AD, the combination of noradrenergic and cholinergic treatments may have a synergistic effect on symptomatic AD. The primary objective of the NorAD trial is to evaluate the change in cognition with 12 weeks of treatment of extended-release guanfacine (GXR) against a placebo as a combination therapy with cholinesterase inhibitors in participants with mild to moderate Alzheimer's disease. METHODS/DESIGN: NorAD is a 3-month, single-centre, randomised, double-blind, placebo-controlled, phase III trial of extended-release guanfacine (GXR) in participants with mild to moderate Alzheimer's disease. A total of 160 participants will be randomised to receive either daily guanfacine or placebo in combination with approved cholinesterase treatment for 12 weeks. The primary outcome is the change in cognition, as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), from baseline to follow-up in the treatment group compared to the placebo group. Secondary outcomes include the change in additional cognitive measures of attention (Tests of Attention: Trails A and B, digit-symbol substitution, Test of Everyday Attention and CANTAB-RVP), neuropsychiatric symptoms (Neuropsychiatric Inventory), caregiver burden (Zarit Burden Interview) and activities of daily living (Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory). From July 2020, observation of change following cessation of treatment is also being assessed. DISCUSSION: There is strong evidence for early noradrenergic dysfunction in Alzheimer's disease. The NorAD trial aims to determine whether guanfacine, a noradrenergic alpha-2 agonist, improves attention and cognition when used in addition to standard cholinergic treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03116126 . Registered on 14 April 2017 EudraCT: 2016-002598-36.

Prevalence of Depressive Symptoms in a Memory Clinic Cohort: A Retrospective Study.

BACKGROUND: Depression has been suggested to be a cause of reversible cognitive impairment but also a risk factor for neurodegenerative disease. Studies suggest that depression prevalence may be high in early onset dementia, particularly Alzheimer's disease, but this has not been systematically assessed in a biomarker-validated clinical dementia cohort to date. OBJECTIVE: To examine the prevalence, features, and association with amyloid pathology of lifetime depressive symptoms in a memory clinic cohort meeting appropriate use criteria for amyloid PET imaging. METHODS: We included 300 patients from a single-center memory clinic cohort that received diagnostic biomarker evaluation with amyloid PET imaging according to appropriate use criteria. History of lifetime depressive symptoms was retrospectively assessed through structured review of clinical correspondence. RESULTS: One hundred forty-two (47%) patients had a history of significant depressive symptoms ('D+'). Of these, 89% had ongoing symptoms and 60% were on antidepressants at the time of presentation to our Clinic. Depressive symptoms were equally highly prevalent in the amyloid-positive and the heterogeneous group of amyloid-negative patients. CONCLUSION: Approximately half of patients who meet appropriate use criteria for amyloid PET have a history of depressive symptoms. We suggest that depression is an important feature of both neurodegenerative and non-neurodegenerative cognitive impairment and may contribute to the diagnostic uncertainty behind referral to amyloid PET.

Multivariate patterns and long-range temporal correlations of alpha oscillations are associated with flexible manipulation of visual working memory representations.

The ability to flexibly manipulate memory representations is embedded in visual working memory (VWM) and can be tested using paradigms with retrospective cues. Although valid retrospective cues often facilitate memory recall, invalid ones may or may not result in performance costs. We investigated individual differences in utilising retrospective cues and evaluated how these individual differences are associated with brain oscillatory activity at rest. At the behavioural level, we operationalised flexibility as the ability to make effective use of retrospective cues or disregard them if required. At the neural level, we tested whether individual differences in such flexibility were associated with properties of resting-state alpha oscillatory activity (8-12 Hz). To capture distinct aspects of these brain oscillations, we evaluated their power spectral density and temporal dynamics using long-range temporal correlations (LRTCs). In addition, we performed multivariate patterns analysis (MVPA) to classify individuals' level of behavioural flexibility based on these neural measures. We observed that alpha power alone (magnitude) at rest was not associated with flexibility. However, we found that the participants' ability to manipulate VWM representations was correlated with alpha LRTC and could be decoded using MVPA on patterns of alpha power. Our findings suggest that alpha LRTC and multivariate patterns of alpha power at rest may underlie some of the individual differences in using retrospective cues in working memory tasks.

Evaluating cognitive profiles of patients undergoing clinical amyloid-PET imaging.

Episodic memory impairment and brain amyloid-beta are two of the main hallmarks of Alzheimer's Disease. In the clinical setting, these are often evaluated through neuropsychological testing and amyloid PET imaging, respectively. The use of amyloid PET in clinical practice is only indicated in patients with substantial diagnostic uncertainty due to atypical clinical presentation, multiple comorbidities and/or early age of onset. The relationship between amyloid-beta and cognition has been previously investigated, but no study has examined how neuropsychological features relate to the presence of amyloid pathology in the clinical population that meets the appropriate use criteria for amyloid PET imaging. In this study, we evaluated a clinical cohort of patients (n = 107) who presented at the Imperial Memory Clinic and were referred for clinical amyloid PET and neuropsychological assessment as part of their diagnostic workup. We compared the cognitive performance of amyloid-positive patients (Aß-pos, n = 47) with that of stable amyloid-negative (stableAß-neg, n = 26) and progressive amyloid-negative (progAß-neg, n = 34) patients. The amyloid-positive group performed significantly worse than both amyloid-negative groups in the visuospatial and working memory domains. Episodic memory performance, however, effectively differentiated the amyloid-positive group from the stable but not the progressive amyloid-negative group. On affective questionnaires, the stable amyloid-negative group reported significantly higher levels of depression than the amyloid-positive group. In our clinical cohort, visuospatial dysfunction and working memory impairment were better indicators of amyloid positivity than episodic memory dysfunction. These findings highlight the limited value of isolated cognitive scores in patients with atypical clinical presentation, comorbidities and/or early age of onset.

The influence of motor preparation on the processing of action-relevant visual features.

Action preparation can facilitate performance in tasks of visual perception, for instance by speeding up responses to action-relevant stimulus features. However, it is unknown whether this facilitation reflects an influence on early perceptual processing, or instead post-perceptual processes. In three experiments, a combination of psychophysics and electroencephalography was used to investigate whether visual features are influenced by action preparation at the perceptual level. Participants were cued to prepare oriented reach-to-grasp actions before discriminating target stimuli oriented in the same direction as the prepared grasping action (congruent) or not (incongruent). As expected, stimuli were discriminated faster if their orientation was congruent, compared to incongruent, with the prepared action. However, action-congruency had no influence on perceptual sensitivity, regardless of cue-target interval and discrimination difficulty. The reaction time effect was not accompanied by modulations of early visual-evoked potentials. Instead, beta-band (13-30 Hz) synchronization over sensorimotor brain regions was influenced by action preparation, indicative of improved response preparation. Together, the results suggest that action preparation may not modulate early visual processing of orientation, but likely influences higher order response or decision related processing. While early effects of action on spatial perception are well documented, separate mechanisms appear to govern non-spatial feature selection.

An evaluation of a working memory training scheme in older adults.

Working memory is a cognitive process that is particularly vulnerable to decline with age. The current study sought to evaluate the efficacy of a working memory training scheme in improving memory in a group of older adults. A 5-week online training scheme was designed to provide training in the main components of Baddeley's (2000) working memory model, namely auditory and visuospatial short-term and working memory. A group of older adults aged between 64 and 79 were randomly assigned to a trainee (n = 19) or control (n = 17) group, with trainees engaging in the adaptive training scheme and controls engaging in a non-adaptive version of the program. Before and after training and at 3- and 6-month follow-up sessions, trainees and controls were asked to complete measures of short-term and working memory, long-term episodic memory, subjective ratings of memory, and attention and achievement of goals set at the beginning of training. The results provided evidence of an expansion of auditory short-term memory span, which was maintained 6 months later, and transfer to long-term episodic memory but no evidence of improvement in working memory capacity per se. A serendipitous and intriguing finding of a relationship between time spent training, psychological stress, and training gains provided further insight into individual differences in training gains in older adults.