Differentiating Prodromal Dementia with Lewy Bodies from Prodromal Alzheimer's Disease: A Pragmatic Review for Clinicians.

This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)-parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners.

The potential role of chronic pain and the polytrauma clinical triad in predicting prodromal PD: A cross-sectional study of U.S. Veterans.

Introduction: The research criteria for prodromal Parkinson disease (pPD) depends on prospectively validated clinical inputs with large effect sizes and/or high prevalence. Neither traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), nor chronic pain are currently included in the calculator, despite recent evidence of association with pPD. These conditions are widely prevalent, co-occurring, and already known to confer risk of REM behavior disorder (RBD) and PD. Few studies have examined PD risk in the context of TBI and PTSD; none have examined chronic pain. This study aimed to measure the risk of pPD caused by TBI, PTSD, and chronic pain. Methods: 216 US Veterans were enrolled who had self-reported recurrent or persistent pain for at least three months. Of these, 44 met criteria for PTSD, 39 for TBI, and 41 for all three conditions. Several pain, sleep, affective, and trauma questionnaires were administered. Participants' history of RBD was determined via self-report, with a subset undergoing confirmatory video polysomnography. Results: A greater proportion of Veterans with chronic pain met criteria for RBD (36 % vs. 10 %) and pPD (18.0 % vs. 8.3 %) compared to controls. Proportions were increased in RBD (70 %) and pPD (27 %) when chronic pain co-occurred with TBI and PTSD. Partial effects were seen with just TBI or PTSD alone. When analyzed as continuous variables, polytrauma symptom severity correlated with pPD probability (r = 0.28, P = 0.03). Conclusion: These data demonstrate the potential utility of chronic pain, TBI, and PTSD in the prediction of pPD, and the importance of trauma-related factors in the pathogenesis of PD.

TIHM: An open dataset for remote healthcare monitoring in dementia.

Dementia is a progressive condition that affects cognitive and functional abilities. There is a need for reliable and continuous health monitoring of People Living with Dementia (PLWD) to improve their quality of life and support their independent living. Healthcare services often focus on addressing and treating already established health conditions that affect PLWD. Managing these conditions continuously can inform better decision-making earlier for higher-quality care management for PLWD. The Technology Integrated Health Management (TIHM) project developed a new digital platform to routinely collect longitudinal, observational, and measurement data, within the home and apply machine learning and analytical models for the detection and prediction of adverse health events affecting the well-being of PLWD. This work describes the TIHM dataset collected during the second phase (i.e., feasibility study) of the TIHM project. The data was collected from homes of 56 PLWD and associated with events and clinical observations (daily activity, physiological monitoring, and labels for health-related conditions). The study recorded an average of 50 days of data per participant, totalling 2803 days.

Lifelong Association of Disorders Related to Military Trauma with Subsequent Parkinson's Disease.

BACKGROUND: Trauma-related disorders such as traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are emerging as risk factors for Parkinson's disease (PD), but their association with development of PD and independence from comorbid disorders remains unknown. OBJECTIVE: To examine TBI and PTSD related to early trauma in military veterans using a case-control study. METHODS: PD was identified by International Classification of Diseases (ICD) code, recurrent PD-specific prescriptions, and availability of 5+ years of earlier records. Validation was performed by chart review by a movement disorder-trained neurologist. Control subjects were matched 4:1 by age, duration of preceding health care, race, ethnicity, birth year, and sex. TBI and PTSD were identified by ICD code and onset based on active duty. Association and interaction were measured for TBI and PTSD with PD going back 60 years. Interaction was measured for comorbid disorders. RESULTS: A total of 71,933 cases and 287,732 controls were identified. TBI and PTSD increased odds of subsequent PD at all preceding 5-year intervals back to year -60 (odds ratio range: 1.5 [1.4, 1.7] to 2.1 [2.0, 2.1]). TBI and PTSD showed synergism (synergy index range: 1.14 [1.09, 1.29] to 1.28 [1.09, 1.51]) and additive association (odds ratio range: 2.2 [1.6, 2.8] to 2.7 [2.5, 2.8]). Chronic pain and migraine showed greatest synergy with PTSD and TBI. Effect sizes for trauma-related disorders were comparable with established prodromal disorders. CONCLUSIONS: TBI and PTSD are associated with later PD and are synergistic with chronic pain and migraine. These findings provide evidence for TBI and PTSD as risk factors preceding PD by decades and could aid in prognostic calculation and earlier intervention. © 2023 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Visual atrophy rating scales and amyloid PET status in an Alzheimer's disease clinical cohort.

OBJECTIVES: Visual rating scales (VRS) are the quantification method closest to the approach used in routine clinical practice to assess brain atrophy. Previous studies have suggested that the medial temporal atrophy (MTA) rating scale is a reliable diagnostic marker for AD, equivalent to volumetric quantification, while others propose a higher diagnostic utility for the Posterior Atrophy (PA) scale in early-onset AD. METHODS: Here, we reviewed 14 studies that assessed the diagnostic accuracy of PA and MTA, we explored the issue of cut-off heterogeneity, and assessed 9 rating scales in a group of patients with biomarker-confirmed diagnosis. A neuroradiologist blinded to all clinical information rated the MR images of 39 amyloid-positive and 38 amyloid-negative patients using 9 validated VRS assessing multiple brain regions. Automated volumetric analyses were performed on a subset of patients (n = 48) and on a group of cognitively normal individuals (n = 28). RESULTS: No single VRS could differentiate amyloid-positive from amyloid-negative patients with other neurodegenerative conditions. 44% of amyloid-positive patients were deemed to have age-appropriate levels of MTA. In the amyloid-positive group, 18% had no abnormal MTA or PA scores. These findings were substantially affected by cut-off selection. Amyloid-positive and amyloid-negative patients had comparable hippocampal and parietal volumes, and MTA but not PA scores correlated with the respective volumetric measures. INTERPRETATION: Consensus guidelines are needed before VRS can be recommended for use in the diagnostic workup of AD. Our data are suggestive of high intragroup variability and non-superiority of volumetric quantification of atrophy over visual assessment.

Task-based differences in brain state dynamics and their relation to cognitive ability.

Transient patterns of interregional connectivity form and dissipate in response to varying cognitive demands. Yet, it is not clear how different cognitive demands influence brain state dynamics, and whether these dynamics relate to general cognitive ability. Here, using functional magnetic resonance imaging (fMRI) data, we characterised shared, recurrent, global brain states in 187 participants across the working memory, emotion, language, and relation tasks from the Human Connectome Project. Brain states were determined using Leading Eigenvector Dynamics Analysis (LEiDA). In addition to the LEiDA-based metrics of brain state lifetimes and probabilities, we also computed information-theoretic measures of Block Decomposition Method of complexity, Lempel-Ziv complexity and transition entropy. Information theoretic metrics are notable in their ability to compute relationships amongst sequences of states over time, compared to lifetime and probability, which capture the behaviour of each state in isolation. We then related task-based brain state metrics to fluid intelligence. We observed that brain states exhibited stable topology across a range of numbers of clusters (K = 2:15). Most metrics of brain state dynamics, including state lifetime, probability, and all information theoretic metrics, reliably differed between tasks. However, relationships between state dynamic metrics and cognitive abilities varied according to the task, the metric, and the value of K, indicating that there are contextual relationships between task-dependant state dynamics and trait cognitive ability. This study provides evidence that the brain reconfigures across time in response to cognitive demands, and that there are contextual, rather than generalisable, relationships amongst task, state dynamics, and cognitive ability.

Remote Monitoring of Physiology in People Living With Dementia: An Observational Cohort Study.

BACKGROUND: Internet of Things (IoT) technology enables physiological measurements to be recorded at home from people living with dementia and monitored remotely. However, measurements from people with dementia in this context have not been previously studied. We report on the distribution of physiological measurements from 82 people with dementia over approximately 2 years. OBJECTIVE: Our objective was to characterize the physiology of people with dementia when measured in the context of their own homes. We also wanted to explore the possible use of an alerts-based system for detecting health deterioration and discuss the potential applications and limitations of this kind of system. METHODS: We performed a longitudinal community-based cohort study of people with dementia using "Minder," our IoT remote monitoring platform. All people with dementia received a blood pressure machine for systolic and diastolic blood pressure, a pulse oximeter measuring oxygen saturation and heart rate, body weight scales, and a thermometer, and were asked to use each device once a day at any time. Timings, distributions, and abnormalities in measurements were examined, including the rate of significant abnormalities ("alerts") defined by various standardized criteria. We used our own study criteria for alerts and compared them with the National Early Warning Score 2 criteria. RESULTS: A total of 82 people with dementia, with a mean age of 80.4 (SD 7.8) years, recorded 147,203 measurements over 958,000 participant-hours. The median percentage of days when any participant took any measurements (ie, any device) was 56.2% (IQR 33.2%-83.7%, range 2.3%-100%). Reassuringly, engagement of people with dementia with the system did not wane with time, reflected in there being no change in the weekly number of measurements with respect to time (1-sample t-test on slopes of linear fit, P=.45). A total of 45% of people with dementia met criteria for hypertension. People with dementia with α-synuclein-related dementia had lower systolic blood pressure; 30% had clinically significant weight loss. Depending on the criteria used, 3.03%-9.46% of measurements generated alerts, at 0.066-0.233 per day per person with dementia. We also report 4 case studies, highlighting the potential benefits and challenges of remote physiological monitoring in people with dementia. These include case studies of people with dementia developing acute infections and one of a person with dementia developing symptomatic bradycardia while taking donepezil. CONCLUSIONS: We present findings from a study of the physiology of people with dementia recorded remotely on a large scale. People with dementia and their carers showed acceptable compliance throughout, supporting the feasibility of the system. Our findings inform the development of technologies, care pathways, and policies for IoT-based remote monitoring. We show how IoT-based monitoring could improve the management of acute and chronic comorbidities in this clinically vulnerable group. Future randomized trials are required to establish if a system like this has measurable long-term benefits on health and quality of life outcomes.

Aciclovir-induced neurotoxicity.

Aciclovir-induced neurotoxicity results from the accumulation of aciclovir and its metabolite 9-carboxymethoxymethylguanine (CMMG). It occurs predominantly in older patients with impaired renal function and is characterised by a combination of confusion and psychiatric changes. Seizures, myoclonus and dysarthria may also occur. Critically, peritoneal dialysis has little effect on reversing the toxic effects of aciclovir. We describe a woman in her 70s with renal failure who developed confusion and seizures after receiving aciclovir. She was ultimately diagnosed with aciclovir-induced neurotoxicity, confirmed by an elevated serum CMMG concentration. This condition is likely to be underdiagnosed and the neurologist's primary challenge is differentiating aciclovir-induced neurotoxicity from viral encephalitis.

A case of clinically aggressive EBV-negative ENKTL in a non-Asian female patient.

BACKGROUND: The patient was a 65-year-old White woman who presented to dermatology with a painless, rapidly growing exophytic nodule on her left upper cheek. AIMS/PURPOSE: In this case report, we aim to demonstrate the difficulty of diagnosing Epstein-Barr virus-negative extranodal NK cell lymphomas given the broad differential of NK cell lymphomas and the rarity of EBV-negative extranodal NK cell lymphoma. METHODS: Immunohistochemical studies confirmed the diagnosis of cutaneous, extranodal NK cell lymphoma. Interestingly, Epstein-Barr virus in situ hybridization was negative, which is unusual for most NK cell lymphomas. RESULTS/CONCLUSIONS: In our view, a combination of immunohistochemistry, clonality assessment, sequencing, and flow cytometric studies is required.

Xenotransplantation of porcine progenitor cells in an epileptic California sea lion (Zalophus californianus): illustrative case.

BACKGROUND: Domoic acid (DA) is a naturally occurring neurotoxin harmful to marine animals and humans. California sea lions exposed to DA in prey during algal blooms along the Pacific coast exhibit significant neurological symptoms, including epilepsy with hippocampal atrophy. OBSERVATIONS: Here the authors describe a xenotransplantation procedure to deliver interneuron progenitor cells into the damaged hippocampus of an epileptic sea lion with suspected DA toxicosis. The sea lion has had no evidence of seizures after the procedure, and clinical measures of well-being, including weight and feeding habits, have stabilized. LESSONS: These preliminary results suggest xenotransplantation has improved the quality of life for this animal and holds tremendous therapeutic promise.

Pathological Slow-Wave Activity and Impaired Working Memory Binding in Post-Traumatic Amnesia.

Associative binding is key to normal memory function and is transiently disrupted during periods of post-traumatic amnesia (PTA) following traumatic brain injury (TBI). Electrophysiological abnormalities, including low-frequency activity, are common following TBI. Here, we investigate associative memory binding during PTA and test the hypothesis that misbinding is caused by pathological slowing of brain activity disrupting cortical communication. Thirty acute moderate to severe TBI patients (25 males; 5 females) and 26 healthy controls (20 males; 6 females) were tested with a precision working memory paradigm requiring the association of object and location information. Electrophysiological effects of TBI were assessed using resting-state EEG in a subsample of 17 patients and 21 controls. PTA patients showed abnormalities in working memory function and made significantly more misbinding errors than patients who were not in PTA and controls. The distribution of localization responses was abnormally biased by the locations of nontarget items for patients in PTA, suggesting a specific impairment of object and location binding. Slow-wave activity was increased following TBI. Increases in the δ-α ratio indicative of an increase in low-frequency power specifically correlated with binding impairment in working memory. Connectivity changes in TBI did not correlate with binding impairment. Working memory and electrophysiological abnormalities normalized at 6 month follow-up. These results show that patients in PTA show high rates of misbinding that are associated with a pathological shift toward lower-frequency oscillations.SIGNIFICANCE STATEMENT How do we remember what was where? The mechanism by which information (e.g., object and location) is integrated in working memory is a central question for cognitive neuroscience. Following significant head injury, many patients will experience a period of post-traumatic amnesia (PTA) during which this associative binding is disrupted. This may be because of electrophysiological changes in the brain. Using a precision working memory test and resting-state EEG, we show that PTA patients demonstrate impaired binding ability, and this is associated with a shift toward slower-frequency activity on EEG. Abnormal EEG connectivity was observed but was not specific to PTA or binding ability. These findings contribute to both our mechanistic understanding of working memory binding and PTA pathophysiology.

The effect of galvanic vestibular stimulation on postural balance in Parkinson's disease: A systematic review and meta-analysis.

People with Parkinson's disease (PD) develop postural imbalance and falls. Galvanic Vestibular Stimulation (GVS) may potentially improve postural balance in humans and hence reduce falls in PD. This systematic review and meta-analysis investigate the effects of GVS on postural balance in PD. Six separate databases and research registers were searched for cross-over design trials that evaluated the effects of GVS on postural balance in PD. We used standardized mean difference (Hedges' g) as a measure of effect size in all studies. We screened 223 studies, evaluated 14, of which five qualified for the meta-analysis. Among n = 40 patients in five studies (range n = 5 to 13), using a fixed effects model we found an effect size estimate of g = 0.43 (p < 0.001, 95% CI [0.29,0.57]). However, the test for residual heterogeneity was significant (p < 0.001), thus we used a random effects model and found a pooled effect size estimate of 0.62 (p > 0.05, 95% CI [- 0.17, 1.41], I2 = 96.21%). Egger's test was not significant and thus trim and funnel plot indicated no bias. To reduce heterogeneity, we performed sensitivity analysis and by removing one outlier study (n = 7 patients), we found an effect size estimate of 0.16 (p < 0.05, 95% CI [0.01, 0.31], I2 = 0%). Our meta-analysis found GVS has a favourable effect on postural balance in PD patients, but due to limited literature and inconsistent methodologies, this favourable effect must be interpreted with caution.

Organisational values of National Health Service trusts in England: semantic analysis and relation to performance indicators.

BACKGROUND: Organisational values are widely assumed to have positive effects on performance and staff. National Health Service (NHS) trusts in England have accordingly chosen their own organisational values. However, there has been no survey of the values adopted, and there is little evidence that the choice of values per se has consequences for outcomes. We comprehensively described trusts' organisational values, using natural language processing to identify common themes. We tested whether the choice of themes was associated with outcomes for patients and staff. METHODS: We collected data on trusts' values (from their websites), performance (Summary Hospital-level Mortality Indicator (SHMI) statistics, Care Quality Commission (CQC) ratings), sickness absence rates (SAR) and staff opinions (NHS Staff Survey responses). We first characterised values based on lexical properties then progressed to semantic analysis, using Google's Universal Sentence Encoder, to transform values to high-dimensional embeddings, and k-means clustering of embeddings to semantically cluster values into 12 common themes. We tested for associations between trusts' use of these themes and outcomes. RESULTS: Organisational values were obtained for 221 of 228 NHS trusts, with 985 values in total (480 unique). Semantic clustering identified themes including 'care', 'value respect' and 'togetherness'. There was no significant association between themes and SHMI or CQC ratings. However, themes predicted trusts' SAR (p=0.001, R2=0.159), with use of 'care', 'value respect', 'aspirational' and 'people' all significant predictors of increased sickness absence; themes also predicted staff opinions on 'Equality, diversity and inclusion' (p=0.011, R2=0.116), but with 'supportive' and 'openness' predicting more negative responses. CONCLUSION: A trust's adoption of individualised organisational values does not seem to make a positive difference to its patients or staff. These findings should give NHS managers pause for thought, challenging them to reconsider their reliance on value-defining initiatives, and to seek evidence that a focus on values has measurable benefits on outcomes.

CRS Diabetes: An Effective Model for Improving Family Medicine Resident Knowledge, Competence, and Performance in Diabetes Care.

The Chief Residents Summit on Intensifying Diabetes Management, now in its 15th year, has resulted in real-world improvements in patient outcomes and has shown itself to be an effective model for teaching diabetes to family medicine residents. This article describes the program and the evidence supporting its effectiveness.

A Novel Mouse Model to Analyze Non-Genomic ERα Physiological Actions.

Nongenomic effects of estrogen receptor α (ERα) signaling have been described for decades. Several distinct animal models have been generated previously to analyze the nongenomic ERα signaling (eg, membrane-only ER, and ERαC451A). However, the mechanisms and physiological processes resulting solely from nongenomic signaling are still poorly understood. Herein, we describe a novel mouse model for analyzing nongenomic ERα actions named H2NES knock-in (KI). H2NES ERα possesses a nuclear export signal (NES) in the hinge region of ERα protein resulting in exclusive cytoplasmic localization that involves only the nongenomic action but not nuclear genomic actions. We generated H2NESKI mice by homologous recombination method and have characterized the phenotypes. H2NESKI homozygote mice possess almost identical phenotypes with ERα null mice except for the vascular activity on reendothelialization. We conclude that ERα-mediated nongenomic estrogenic signaling alone is insufficient to control most estrogen-mediated endocrine physiological responses; however, there could be some physiological responses that are nongenomic action dominant. H2NESKI mice have been deposited in the repository at Jax (stock no. 032176). These mice should be useful for analyzing nongenomic estrogenic responses and could expand analysis along with other ERα mutant mice lacking membrane-bound ERα. We expect the H2NESKI mouse model to aid our understanding of ERα-mediated nongenomic physiological responses and serve as an in vivo model for evaluating the nongenomic action of various estrogenic agents.

Airway Sensory Nerve Plasticity in Asthma and Chronic Cough.

Airway sensory nerves detect a wide variety of chemical and mechanical stimuli, and relay signals to circuits within the brainstem that regulate breathing, cough, and bronchoconstriction. Recent advances in histological methods, single cell PCR analysis and transgenic mouse models have illuminated a remarkable degree of sensory nerve heterogeneity and have enabled an unprecedented ability to test the functional role of specific neuronal populations in healthy and diseased lungs. This review focuses on how neuronal plasticity contributes to development of two of the most common airway diseases, asthma and chronic cough, and discusses the therapeutic implications of emerging treatments that target airway sensory nerves.