Perspectives and challenges in patient stratification in Alzheimer's disease.

BACKGROUND: Patient stratification is the division of a patient population into distinct subgroups based on the presence or absence of particular disease characteristics. As patient stratification can be used to account for the underlying pathology of a disease, it can help physicians to tailor therapeutic interventions to individuals and optimize their care management and treatment regime. Alzheimer's disease, the most common form of dementia, is a heterogeneous disease and its management benefits from patient stratification in clinical trials, and the development of personalized care and treatment strategies for people living with the disease. MAIN BODY: In this review, we discuss the importance of the stratification of people living with Alzheimer's disease, the challenges associated with early diagnosis and patient stratification, and the evolution of patient stratification once disease-modifying therapies become widely available. CONCLUSION: Patient stratification plays an important role in drug development in clinical trials and may play an even larger role in clinical practice. A timely diagnosis and stratification of people living with Alzheimer's disease is paramount in determining people who are at risk of progressing from mild cognitive impairment to Alzheimer's dementia. There are key issues associated with stratifying patients which include the heterogeneity and complex neurobiology behind Alzheimer's disease, our inadequately prepared healthcare systems, and the cultural perceptions of Alzheimer's disease. Stratifying people living with Alzheimer's disease may be the key in establishing precision and personalized medicine in the field, optimizing disease prevention and pharmaceutical treatment to slow or stop cognitive decline, while minimizing adverse effects.

Alzheimer's disease diagnosis and management: Perspectives from around the world.

Alzheimer's disease (AD) and other dementias are a global challenge. Early diagnosis is important to manage the disease. However, there are barriers to diagnosis that differ by region. Researchers from Brazil, China, Nigeria, Spain, and Sweden have identified key barriers to AD diagnosis in their countries. In Brazil, socioeconomic inequalities and poor recognition of dementia by physicians can prevent diagnosis. In China, a very large population and lack of physician training in dementia make diagnosis problematic. In Nigeria, socioeconomic inequalities and cultural stigma can stand in the way of diagnosis. In Spain, patient hesitancy and an overloaded health-care system are barriers to diagnosis. In Sweden, inconsistent use of biomarkers is a prominent barrier to diagnosis of AD. To support diagnosis, more focus is needed on education of patients and physicians, increased use of support services, and improved access to biomarkers to accurately diagnose AD.

Brain amyloid, cortical thickness, and changes in activities of daily living.

OBJECTIVE: To examine the association of baseline elevated brain amyloid and neurodegeneration with changes in activities of daily living in participants without dementia (ND; i.e., cognitively unimpaired and participants with mild cognitive impairment) at baseline in the population-based Mayo Clinic Study of Aging. METHODS: We included 1747 ND participants with 11 C-PiB PET and MR imaging in the study, with data on activities of daily living (as assessed by the Functional Activities Questionnaire (FAQ) and the Clinical Dementia Rating scale Sum of Boxes for functional domains (CDR-SOB (functional)), with a median (range) of 4.3 (0.0-12.7) years of follow-up. Abnormal (elevated; A+) 11 C-PiB-PET retention ratio was defined as standardized uptake value ratio ≥ 1.48, and abnormal (reduced) AD signature cortical thickness as ≤ 2.68 mm (neurodegeneration; N+). Associations were examined with mixed effects models, adjusting for age, sex, education, apolipoprotein E ε4 allele carrier status, and global cognitive z-score. RESULTS: Mean age (SD) was 71.4 years (10.1), 46.7% were females, 195 (11.2%) had A+N-, 442 (25.3%) had A-N+, and 339 (19.4%) had A+N+ biomarkers. The A+N+ group had the largest annualized change in the FAQ score from baseline (difference in annual change A+N+ vs. A-N-; ß (SE): 0.80 (0.07)); associations were substantially attenuated when a time-varying global cognitive composite was included in the model (A+N+ vs. A-N-; ß (SE): 0.31 (0.05)). CDR-SOB (functional) findings partly agreed with FAQ score findings. INTERPRETATION: The longitudinal increase in functional limitations is greater for individuals with abnormal neuroimaging biomarkers, especially for those with both elevated brain amyloid and neurodegeneration.

Evolution to a Competency-Based Training Curriculum for Pharmaceutical Medicine Physicians in Switzerland.

In Switzerland, Pharmaceutical Medicine has existed as one of 46 physician specialties accredited by the Federal Office of Public Health for more than 20 years. As a medical-scientific discipline, our goal is to enable best possible therapeutic coverage for the benefit of patients and society through a medical need-based development and optimal use of medicinal products. The role of the specialist in Pharmaceutical Medicine is to closely collaborate with various stakeholders of the healthcare system in the context of the discovery, research, development and approval of new medicinal products, as well as safe and effective use of new and established medicinal products in daily clinical practice. The post-graduate training consists of 2 years of patient-related clinical work, followed by 3 years of vocational training at certified training centers in Pharmaceutical Medicine. This also includes completion of an academic post-graduate diploma in Pharmaceutical Medicine (30 ECTS) according to the IFAPP/PharmaTrain syllabus and a 1 day board exam. As part of an ongoing revision of the training curriculum, we are developing a Swiss Catalog of Core Competencies in Pharmaceutical Medicine (SC3-PM), based on the IFAPP competency framework for drug development specialists in industry. In this article we discuss how we adapt the scope of the IFAPP competency framework to better reflect such roles in academic institutions or regulatory bodies in Switzerland.

Cortical ß-amyloid burden, neuropsychiatric symptoms, and cognitive status: the Mayo Clinic Study of Aging.

Neuropsychiatric symptoms (NPS) are a risk factor for cognitive impairment and are associated with cortical ß-amyloid (Aß) deposition. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging to examine the frequency of NPS among cognitively unimpaired (CU) and mild cognitive impairment (MCI) participants who either have normal (A-) or abnormal (A+) Aß deposition. We also investigated whether combined presence of MCI and amyloid positivity (MCI/A+) is associated with greater odds of having NPS as compared to CU/A- (defined as reference group). Participants were 1627 CU and MCI individuals aged ≥ 50 years (54% males; median age 73 years). All participants underwent NPS assessment (Neuropsychiatric Inventory Questionnaire (NPI-Q); Beck Depression Inventory II (BDI-II); Beck Anxiety Inventory (BAI)) and 11C-PiB-PET. Participants with an SUVR > 1.42 were classified as A+. We conducted multivariable logistic regression analyses adjusted for age, sex, education, and APOE ε4 genotype status. The sample included 997 CU/A-, 446 CU/A+, 78 MCI/A-, and 106 MCI/A+ persons. For most NPS, the highest frequency of NPS was found in MCI/A+ and the lowest in CU/A-. The odds ratios of having NPS, depression (BDI ≥ 13), or anxiety (BAI ≥ 8, ≥ 10) were consistently highest for MCI/A+ participants. In conclusion, MCI with Aß burden of the brain is associated with an increased risk of having NPS as compared to MCI without Aß burden. This implies that the underlying Alzheimer's disease biology (i.e., cerebral Aß amyloidosis) may drive both cognitive and psychiatric symptoms.

Swiss analysis of multiple sclerosis: a multicenter, non-interventional, retrospective cohort study of disease-modifying therapies.

BACKGROUND: There is a scarcity of reports comparing efficacy and tolerability of the multiple sclerosis (MS) disease-modifying therapies [DMTs; intramuscular interferon-ß1a (IM IFNß-1a), subcutaneous (SC) IFNß-1a, SC IFNß-1b, SC glatiramer acetate (GA)] in a real-world setting. METHODS: This multicenter, non-interventional, retrospective cohort study analyzed data from 546 patients with clinically isolated or relapsing-remitting MS constantly treated with one DMT for 2 years. Annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) scores, and DMT tolerability were assessed. RESULTS: Demographic data were comparable across DMTs. There were no significant differences between DMT groups in ARR during study year 1 (p = 0.277) or study year 2 (p = 0.670), or in EDSS change between years 1 and 2 (p = 0.624). Adverse events were frequent (39-56%) in all groups. Flu-like symptoms were less frequent with GA treatment (2.3% vs. IM IFNß-1a, 46.7%; SC IFNß-1a, 39.8%; SC IFNß-1b, 25.8%; p < 0.05). Injection site reactions were less often reported with IM IFNß-1a (10.5% vs. SC IFNß-1a, 33.9%; SC IFNß-1b, 38.3%; GA, 26.1%; p < 0.05). CONCLUSIONS: All DMTs showed comparable effects on MS relapse rate and EDSS change, with IM IFNß-1a and GA being more tolerable with respect to injection site reactions and flu-like symptoms, respectively.

[Characteristics of patients suffering from chronic pain with depressive symptoms in three different treatment settings]. / Charakteristika chronischer Schmerzpatienten mit depressiver Begleitsymptomatik in drei unterschiedlichen Behandlungssettings.

BACKGROUND: Only few studies considered demographic and medical characteristics of pain patients with depressive symptoms. METHODS: The present study is a cross-sectional observation of 585 patients suffering from chronic pain and depressive symptoms from all over Switzerland who got an antidepressant treatment in 122 medical practices (internal medicine, general medicine, psychiatry). Based on their clinical experience within the Swiss mental health system, the authors hypothesized that internists and general practitioners, compared to psychiatrists, treat older and less depressive patients with less intense chronic pain and with regional origin from Central Europe. RESULTS: In accordance with this hypothesis, internists (and general practitioners), compared to psychiatrists, more frequently provided care for older patients from Central Europe with less severe depressive symptoms and lower pain intensity and less head pain. Furthermore, compared with Central European patients, those patients from Eastern and Southern Europe presented more intense overall pain mainly affecting the head, extremities, back, and thorax whereas Southern Europeans tended to suffer even more frequently from chest pain compared with their Central European peers. CONCLUSION: The study design pragmatically represents the caring situation for depressed patients with chronic pain in Switzerland regarding regional origin and pain intensity. The results are based on a respectable sample size recruited from all Swiss regions and by the physician specialities primarily involved in long-term management of this patient group.

Regional origin and decrease of pain in patients with depressive symptoms under treatment with venlafaxine.

OBJECTIVE: Patient's language, tradition, conventions, and customs may all determine integration into a society and are also part of the doctor-patient relationship that influences diagnostic and therapeutic outcome. Language barrier and sociocultural disparity of Eastern and Southern European patients may hamper recovery from pain and depression compared to Middle European patients in Switzerland. METHODS: In a prospective naturalistic observational trial we investigated the influence of regional origin on treatment outcome in 420 pain sufferers with depressive symptoms from all over Switzerland who were treated with venlafaxine by 122 physicians in primary care. Physicians rated severity of depressive symptoms using the clinical global impression severity scale and pain intensity by means of visual analogue scales. We hypothesized that in Eastern and Southern European patients the magnitude of pain reduction under treatment with venlafaxine is less compared to Middle European patients. RESULTS: Three months after study entry, Middle European patients were found to profit more from treatment with venlafaxine in terms of severity of depression and pain intensity than patients from Eastern Europe and Southern Europe. CONCLUSION: Regional origin may contribute to the magnitude of pain reduction in patients with depressive symptoms under treatment with venlafaxine. Our results provide a rational for care provider educational programs aimed at improving capacities in treating patients from different regional origin with psychosomatic complaints such as depression and comorbid pain.

Change in pain severity with open label venlafaxine use in patients with a depressive symptomatology: an observational study in primary care.

PURPOSE: Venlafaxine has shown benefit in the treatment of depression and pain. Worldwide data are extensively lacking investigating the outcome of chronic pain patients with depressive symptoms treated by venlafaxine in the primary care setting. This observational study aimed to elucidate the efficacy of venlafaxine and its prescription by Swiss primary care physicians and psychiatrists in patients with chronic pain and depressive symptomatology. SUBJECTS AND METHODS: We studied 505 patients with depressive symptoms suffering from chronic pain in a prospective naturalistic Swiss community based observational trial with venlafaxine in primary care. These patients have been treated with venlafaxine by 122 physicians, namely psychiatrists, general practitioners, and internists. RESULTS: On average, patients were treated with 143+/-75 mg (0-450 mg) venlafaxine daily for a follow-up of three months. Venlafaxine proved to be beneficial in the treatment of both depressive symptoms and chronic pain. DISCUSSION: Although side effects were absent in most patients, physicians might have frequently omitted satisfactory response rate of depression by underdosing venlafaxine. Our results reflect the complexity in the treatment of chronic pain in patients with depressive symptoms in primary care. CONCLUSION: Further randomized dose-finding studies are needed to learn more about the appropriate dosage in treating depression and comorbid pain with venlafaxine.