A Comparison Between Early Presentation of Dementia with Lewy Bodies, Alzheimer's Disease, and Parkinson's Disease: Evidence from Routine Primary Care and UK Biobank Data.

OBJECTIVE: The purpose of this study was to simultaneously contrast prediagnostic clinical characteristics of individuals with a final diagnosis of dementia with Lewy Bodies (DLB), Parkinson's disease (PD), and Alzheimer's disease (AD) compared with controls without neurodegenerative disorders. METHODS: Using the longitudinal THIN database in the United Kingdom, we tested the association of each neurodegenerative disorder with a selected list of symptoms and broad families of treatments, and compared the associations between disorders to detect disease-specific effects. We replicated the main findings in the UK Biobank. RESULTS: We used data of 28,222 patients with PD, 20,214 with AD, 4,682 with DLB, and 20,214 healthy controls. All neurodegenerative disorders were significantly associated with the presence of multiple clinical characteristics before their diagnosis, including sleep disorders, falls, psychiatric symptoms, and autonomic dysfunctions. When comparing patients with DLB with patients with PD and patients with AD patients, falls, psychiatric symptoms, and autonomic dysfunction were all more strongly associated with DLB in the 5 years preceding the first neurodegenerative diagnosis. The use of statins was lower in patients who developed PD and higher in patients who developed DLB compared to patients with AD. In patients with PD, the use of statins was associated with the development of dementia in the 5 years following PD diagnosis. INTERPRETATION: Prediagnostic presentations of falls, psychiatric symptoms, and autonomic dysfunctions were more strongly associated with DLB than PD and AD. This study also suggests that although several associations with medications are similar in neurodegenerative disorders, statin usage is negatively associated with PD but positively with DLB and AD as well as development of dementia in PD. ANN NEUROL 2023;94:259-270.

Identifying health conditions associated with Alzheimer's disease up to 15 years before diagnosis: an agnostic study of French and British health records.

BACKGROUND: The identification of modifiable risk factors for Alzheimer's disease is paramount for early prevention and the targeting of new interventions. We aimed to assess the associations between health conditions diagnosed in primary care and the risk of incident Alzheimer's disease over time, up to 15 years before a first Alzheimer's disease diagnosis. METHODS: In this agnostic study of French and British health records, data from 20 214 patients with Alzheimer's disease in the UK and 19 458 patients with Alzheimer's disease in France were extracted from The Health Improvement Network database. We considered data recorded from Jan 1, 1996, to March 31, 2020 in the UK and from Jan 4, 1998, to Feb 20, 2019, in France. For each Alzheimer's disease case, a control was randomly assigned after matching for sex and age at last visit. We agnostically tested the associations between 123 different diagnoses of the International Classification of Diseases, 10th revision, extracted from health records, and Alzheimer's disease, by running a conditional logistic regression to account for matching of cases and controls. We focused on three time periods before diagnosis of Alzheimer's disease, to separate risk factors from early symptoms and comorbidities. FINDINGS: Unadjusted odds ratios (ORs) and 95% CIs for the association between Alzheimer's disease and various health conditions were estimated, and p values were corrected for multiple comparisons. In both the British and French studies, ten health conditions were significantly positively associated with increased Alzheimer's disease risk, in a window of exposure from 2-10 years before Alzheimer's disease diagnosis, comprising major depressive disorder (UK OR 1·34, 95% CI 1·23-1·46; France OR 1·73, 1·57-1·91), anxiety (UK OR 1·36, 1·25-1·47; France OR 1·50, 1·36-1·65), reaction to severe stress and adjustment disorders (UK OR 1·40, 1·24-1·59; France OR 1·83, 1·55-2·15), hearing loss (UK OR 1·19, 1·11-1·28; France OR 1·51, 1·21-1·89), constipation (UK OR 1·31, 1·22-1·41; France OR 1·59, 1·44-1·75), spondylosis (UK OR 1·26, 1·14-1·39; France OR 1·62, 1·44-1·81), abnormal weight loss (UK OR 1·47, 1·33-1·63; France OR 1·88, 1·56-2·26), malaise and fatigue (UK OR 1·23, 1·14-1·32; France OR 1·59, 1·46-1·73), memory loss (UK OR 7·63, 6·65-8·76; France OR 4·41, 3·07-6·34), and syncope and collapse (UK OR 1·23, 1·10-1·37; France OR 1·57, 1·26-1·96). Depression was the first comorbid condition associated with Alzheimer's disease, appearing at least 9 years before the first clinical diagnosis, followed by anxiety, constipation, and abnormal weight loss. INTERPRETATION: These results from two independent primary care databases provide new evidence on the temporality of risk factors and early signs of Alzheimer's disease that are observable at the general practitioner level. These results could guide the implementation of new primary and secondary prevention policies. FUNDING: Agence Nationale de la Recherche.

Unintentional exposure to pregabalin in ≤6-year-old children: a nationwide French Poison Control Center study.

INTRODUCTION: In France, pregabalin is widely prescribed in adults but still not approved for children. We aimed to investigate the incidence of pregabalin exposure in ≤6-year-old children, to describe the characteristics and outcome of ingestions involving pregabalin alone, and to estimate a clinically relevant toxic dose in this population. METHODS: Retrospective analysis of pregabalin exposures in ≤6-year-old children, collected by the French Poison Control Centers in 2004-2019. The incidence was estimated using pregabalin prescription data from the Health Improvement Network database (the French version of THIN). The poison severity score (PSS) was used to grade severity. RESULTS: We found 313 unintentional immediate-release pregabalin ingestions in ≤6-year-old children. The number of cases per 100,000 pregabalin-treated adults increased over time (p < 0.001). One hundred twenty-six cases involving pregabalin alone (age, 2 years [1.6-3.0] (median [25th-75th percentiles]); median ingested dose 6.4 mg/kg [3.6-10.9]) were analyzed. No child presented an underlying neurological/cardiac disease and/or took concomitant medications. Most of the children (77%) remained asymptomatic (PSS0) while 21% and 2% developed minor (PSS1) or moderate (PSS2) neurological symptoms, respectively. No severe complications/fatalities were reported. All symptomatic children recovered within 24 h. The ingested pregabalin dose was positively correlated with PSS (p < 0.0001). Using a ROC curve approach (area under the curve, 0.85; p < 0.001), ingestion of ≥19.4 mg/kg pregabalin was appropriate to recommend hospital referral (sensitivity, 39% [95% confidence interval (95% CI), 24-56], specificity, 100% [95% CI, 96-100], predictive positive value, 100% [95% CI, 64-100], and negative predictive value, 85% [95% CI, 82-89]). Symptomatic children who ingested <19.4 mg/kg pregabalin developed minor symptoms. CONCLUSION: Despite increasing prescriptions in adults in France, unintentional pregabalin ingestions in ≤6-year-old children remain rare and cause minimal toxicity. Children with no underlying neurological/cardiac disease and concomitant medication ingesting <19.4 mg/kg immediate-release pregabalin alone can be safely observed at home.