Feasibility of a standard cognitive assessment in European academic memory clinics.

INTRODUCTION: Standardized cognitive assessment would enhance diagnostic reliability across memory clinics. An expert consensus adapted the Uniform Dataset (UDS)-3 for European centers, the clinician's UDS (cUDS). This study assessed its implementation acceptability and feasibility. METHODS: We developed a survey investigating barriers, facilitators, and willingness to implement the cUDS. With a mixed-methods design, we analyzed data from academic memory clinics. RESULTS: Seventy-eight percent of responding clinicians were experienced neuropsychologists/psychologists and 22% were medical specialists coming from 18 European countries. Sixty-five percent clinicians were willing to implement cUDS. General barriers related to implementation (43%) and clinical-methodological domains (21%). Favorable clinicians reported finances (15%) and digitalization (9%) as facilitating, but unavailability of local norms (23%) as hindering. Unfavorable clinicians reported logistical (23%) and time issues (18%). DISCUSSION: Despite challenges, data showed moderate clinicians' acceptability and requirements to improve feasibility. Nonetheless, these results come from academic clinicians. The next steps will require feasibility evaluation in non-academic contexts.

Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer's disease therapeutic.

In vivo biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-ß pathology as well as its effects on downstream processes associated with Alzheimer's disease pathophysiology. Here, we applied an in vivo longitudinal study design combined with imaging and cerebrospinal fluid biomarkers, mirroring those used in human clinical trials to assess the efficacy of a novel brain-penetrating anti-amyloid fusion protein treatment in the McGill-R-Thy1-APP transgenic rat model. The bi-functional fusion protein consisted of a blood-brain barrier crossing single domain antibody (FC5) fused to an amyloid-ß oligomer-binding peptide (ABP) via Fc fragment of mouse IgG (FC5-mFc2a-ABP). A five-week treatment with FC5-mFc2a-ABP (loading dose of 30 mg/Kg/iv followed by 15 mg/Kg/week/iv for four weeks) substantially reduced brain amyloid-ß levels as measured by positron emission tomography and increased the cerebrospinal fluid amyloid-ß42/40 ratio. In addition, the 5-week treatment rectified the cerebrospinal fluid neurofilament light chain concentrations, resting-state functional connectivity, and hippocampal atrophy measured using magnetic resonance imaging. Finally, FC5-mFc2a-ABP (referred to as KG207-M) treatment did not induce amyloid-related imaging abnormalities such as microhemorrhage. Together, this study demonstrates the translational values of the designed preclinical studies for the assessment of novel therapies based on the clinical biomarkers providing tangible metrics for designing early-stage clinical trials.

CCCDTD5 recommendations on early and timely assessment of neurocognitive disorders using cognitive, behavioral, and functional scales.

INTRODUCTION: Earlier diagnosis of neurocognitive disorders and neurodegenerative disease is needed to implement preventative interventions, minimize harm, and reduce risk of exploitation in the context of undetected disease. Along the spectrum from subjective cognitive decline (SCD) to dementia, evidence continues to emerge with respect to detection, staging, and monitoring. Updates to previous guidelines are required for clinical practice. METHODS: A subcommittee of the 5th Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD) reviewed emerging evidence to address the following: (1) Is there a role for screening at-risk patients without clinical concerns? In what context is assessment for dementia appropriate? (2) What tools can be used to evaluate patients in whom cognitive decline is suspected? (3) What important information can be gained from an informant, using which measures? (4) What instruments can be used to get more in-depth information to diagnose mild cognitive impairment (MCI) or dementia? (5) What is the approach to those with cognitive concerns but without objective changes (ie, SCD)? (6) How do we track response to treatment and change over time? The Grading of Recommendations Assessment, Development, and Evaluation system was used to rate quality of the evidence and strength of the recommendations. RESULTS: We recommend instruments to assess and monitor cognition, behavior, and function across the cognitive spectrum, including reports from patient and informant. We recommend against screening asymptomatic older adults but recommend investigation for self- or informant reports of changes in cognition, emergence of behavioral or psychiatric symptoms, or decline in function or self-care. Standardized assessments should be used for cognitive and behavioral change that have sufficient validity for use in clinical practice. DISCUSSION: The CCCDTD5 provides evidence-based recommendations for detection, assessment, and monitoring of neurocognitive disorders. Although these guidelines were developed for use in Canada, they may also be useful in other jurisdictions.

Remote cognitive and behavioral assessment: Report of the Alzheimer Society of Canada Task Force on dementia care best practices for COVID-19.

INTRODUCTION: Despite the urgent need for remote neurobehavioral assessment of individuals with cognitive impairment, guidance is lacking. Our goal is to provide a multi-dimensional framework for remotely assessing cognitive, functional, behavioral, and physical aspects of people with cognitive impairment, along with ethical and technical considerations. METHODS: Literature review on remote cognitive assessment and multidisciplinary expert opinion from behavioral neurologists, neuropsychiatrists, neuropsychologists, and geriatricians was integrated under the auspices of the Alzheimer Society of Canada Task Force on Dementia Care Best Practices for COVID-19. Telephone and video approaches to assessments were considered. RESULTS: Remote assessment is shown to be acceptable to patients and caregivers. Informed consent, informant history, and attention to privacy and autonomy are paramount. A range of screening and domain-specific instruments are available for telephone or video assessment of cognition, function, and behavior. Some neuropsychological tests administered by videoconferencing show good agreement with in-person assessment but still lack validation and norms. Aspects of the remote dementia-focused neurological examination can be performed reliably. DISCUSSION: Despite challenges, current literature and practice support implementation of telemedicine assessments for patients with cognitive impairment. Convergence of data across the clinical interview, reliable and brief remote cognitive tests, and remote neurological exam increase confidence in clinical interpretation and diagnosis.

Dementia in China: epidemiology, clinical management, and research advances.

China has the largest population of patients with dementia in the world, imposing a heavy burden on the public and health care systems. More than 100 epidemiological studies on dementia have been done in China, but the estimates of the prevalence and incidence remain inconsistent because of the use of different sampling methods. Despite improved access to health services, inadequate diagnosis and management for dementia is still common, particularly in rural areas. The Chinese Government issued a new policy to increase care facilities for citizens older than 65 years, but most patients with dementia still receive care at home. Western medicines for dementia symptoms are widely used in China, but many patients choose Chinese medicines even though they have little evidence supporting efficacy. The number of clinical trials of Chinese and western medicines has substantially increased as a result of progress in research on new antidementia drugs but international multicentre studies are few in number. Efforts are needed to establish a national system of dementia care enhance training in dementia for health professionals, and develop global collaborations to prevent and cure this disease.

The Comprehensive Assessment of Neurodegeneration and Dementia: Canadian Cohort Study.

BACKGROUND: The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams. METHODS: The COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here. RESULTS: The CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020. CONCLUSION: Availability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years.

Évaluation complète d'une étude de cohorte canadienne portant sur la démence et la neuro-dégénérescence. Contexte : L'évaluation globale de la neuro-dégénérescence et de la démence (COMPASS-ND), étude de cohorte du Consortium canadien en neuro-dégénérescence associée au vieillissement (CCNV), représente une initiative nationale visant à promouvoir la recherche portant sur la démence et à soutenir les programmes de recherche des équipes du CCNV. Totalisant 2310 sujets recrutés partout au pays, cette cohorte longitudinale regroupe des individus fortement « phénotypés ¼ qui présentent diverses formes de démence et de pertes de mémoire légères. En plus de sujets âgés dont les fonctions cognitives sont intactes, ces 2310 sujets ont permis de valider les hypothèses formulées par les équipes du CCNV. Méthodes : Nous avons utilisé de nombreux documents pour décrire cette étude : le protocole de la COMPASS-ND ; la demande initiale de subvention ; le cinquième rapport d'étape semi-annuel du CCNV soumis aux Instituts de recherche en santé du Canada (IRSC) en décembre 2017 ; ainsi que d'autres documents produits à la suite de modifications consécutives à la mise en œuvre de ce projet. Résultats: L'étude de cohorte COMPASS-ND du CCNV inclut des participants de partout au Canada dont les divers états cognitifs sont associés à des maladies neurodégénératives ou au risque d'en souffrir. Ils feront l'objet d'un large éventail d'examens expérimentaux, cliniques, génétiques et d'imagerie afin d'aborder de manière spécifique les causes, le diagnostic, le traitement et la prévention de ces états cognitifs chez les personnes âgées. Les données obtenues à la suite d'évaluations cliniques et cognitives, ainsi que celles issues d'échantillons biologiques, d'imagerie cérébrale, de tests génétiques et de dons de cerveaux, seront utilisées pour tester les hypothèses générées par les équipes de recherche du CCNV et d'autres chercheurs canadiens. Cette étude constitue donc à ce jour l'étude canadienne la plus complète et la plus ambitieuse au sujet de la démence. La présentation des données initiales ayant eu lieu en 2018, la cohorte devrait atteindre sa taille maximale d'ici à 2020.Conclusion : La disponibilité des données de l'étude COMPASS-ND stimulera considérablement la recherche sur la démence au Canada au cours des prochaines années.

The influence of language and culture on cognitive assessment tools in the diagnosis of early cognitive impairment and dementia.

INTRODUCTION: Cognitive assessment tools measure cognitive impairment and complement biomarkers to link cognitive symptoms with pathophysiological processes underlying dementia. However, language and cultural differences in multilingual populations can influence the interpretation of cognitive assessment tools when applied in cross-cultural and multinational studies. Areas covered: This article examines the influence of culture and language on the interpretation of the Mini-Mental State Examination, Montreal Cognitive Assessment, and Alzheimer's Disease Assessment Scale-cognitive subscale, which are more commonly used worldwide. It discusses how this impacted multinational studies. Lastly, it presents language-neutral tools such as the Visual Cognitive Assessment Test, which do not require translation when applied in multilingual populations. Expert commentary: Linguistic and cultural variation within tools due to translation and differences in administration introduce method bias and differential item functioning, which influence the interpretation of cognitive scores in multinational studies. The ultimate goal is to have a tool that accurately measures cognitive impairment, yet with minimal influence from linguistic, cultural, educational, and demographic differences, through concerted international efforts to harmonize the development and validation of tools. While recently developed visual-based language-neutral tools show promise in the early detection of cognitive impairment, further validation will be required for these tools to be applied internationally.

The cost of Alzheimer's disease in China and re-estimation of costs worldwide.

INTRODUCTION: The socioeconomic costs of Alzheimer's disease (AD) in China and its impact on global economic burden remain uncertain. METHODS: We collected data from 3098 patients with AD in 81 representative centers across China and estimated AD costs for individual patient and total patients in China in 2015. Based on this data, we re-estimated the worldwide costs of AD. RESULTS: The annual socioeconomic cost per patient was US $19,144.36, and total costs were US $167.74 billion in 2015. The annual total costs are predicted to reach US $507.49 billion in 2030 and US $1.89 trillion in 2050. Based on our results, the global estimates of costs for dementia were US $957.56 billion in 2015, and will be US $2.54 trillion in 2030, and US $9.12 trillion in 2050, much more than the predictions by the World Alzheimer Report 2015. DISCUSSION: China bears a heavy burden of AD costs, which greatly change the estimates of AD cost worldwide.

Burden, anxiety and depression in caregivers of veterans with dementia in Beijing.

Dementia is the most common neurodegenerative disease in the elderly. The number of Chinese dementia patients reached 5 million in 2001 and will grow rapidly by 314-336% in 2040. Caring for patients with dementia is a stressful experience, which can cause the physical and mental problems in caregivers. According to the protocol, we evaluated the burden, depression and anxiety of caregivers by Clinical Dementia Rating (CDR) Scale, Caregiver Burden Inventory (CBI), Self-Rating Depression Scale (SDS) and Self-Rating Anxiety Scale (SAS). 90 caregivers of dementia patients and 90 caregivers of nondementia patients with other chronic diseases from 24 military communities in Beijing were enrolled in this investigation. The scores of burden, depression and anxiety increased from nondementia to severe dementia groups. There were associations between patient's CDR score and CBI score, as well as the average daily care time and CBI score. In addition, the scores of SDS and SAS were both positive correlated to CBI score. Comparing to general community, the caregivers of dementia veterans had lower scores in SDS and SAS. Therefore, we should pay more attentions to the caregivers of severe dementia patients. Reduction of daily care time is a possible way to releasing the burden of caregivers. Better general supports are beneficial to reducing depression and anxiety when caregivers confront the heavy burden.

Collaborative research between academia and industry using a large clinical trial database: a case study in Alzheimer's disease.

BACKGROUND: Large clinical trials databases, developed over the course of a comprehensive clinical trial programme, represent an invaluable resource for clinical researchers. Data mining projects sponsored by industry that use these databases, however, are often not viewed favourably in the academic medical community because of concerns that commercial, rather than scientific, goals are the primary purpose of such endeavours. Thus, there are few examples of sustained collaboration between leading academic clinical researchers and industry professionals in a large-scale data mining project. We present here a successful example of this type of collaboration in the field of dementia. METHODS: The Donepezil Data Repository comprised 18 randomised, controlled trials conducted between 1991 and 2005. The project team at Pfizer determined that the data mining process should be guided by a diverse group of leading Alzheimer's disease clinical researchers called the "Expert Working Group." After development of a list of potential faculty members, invitations were extended and a group of seven members was assembled. The Working Group met regularly with Eisai/Pfizer clinicians and statisticians to discuss the data, identify issues that were currently of interest in the academic and clinical communities that might lend themselves to investigation using these data, and note gaps in understanding or knowledge of Alzheimer's disease that these data could address. Leadership was provided by the Pfizer Clinical Development team leader; Working Group members rotated responsibility for being lead and co-lead for each investigation and resultant publication. RESULTS: Six manuscripts, each published in a leading subspecialty journal, resulted from the group's work. Another project resulted in poster presentations at international congresses and two were cancelled due to resource constraints. CONCLUSIONS: The experience represents a particular approach to optimising the value of data mining of large clinical trial databases for the combined purpose of furthering clinical research and improving patient care. Fruitful collaboration between industry and academia was fostered while the donepezil data repository was used to advance clinical and scientific knowledge. The Expert Working Group approach warrants consideration as a blueprint for conducting similar research ventures in the future.

Validation of the relevant outcome scale for Alzheimer's disease: a novel multidomain assessment for daily medical practice.

INTRODUCTION: The Relevant Outcome Scale for Alzheimer's Disease (ROSA) is a new observer rating instrument recently developed for routine medical practice. The validity and reliability of ROSA as well as sensitivity to changes due to intervention were examined in an open-label, single-arm, multicenter clinical study in patients with Alzheimer's disease (AD). METHODS: The study enrolled 471 patients with a diagnosis of AD consistent with the criteria of the National Institute of Neurological and Communicative Disease and Stroke/Alzheimer's Disease and Related Disorders Association or with the Diagnostic and Statistical Manual Disorders criteria for dementia of Alzheimer's type. Following assessments of the ROSA and other standard assessments (Alzheimer's Disease Assessment Scale - cognitive subscale, Severe Impairment Battery, Neuropsychiatric Inventory, and Disability Assessment for Dementia), patients were treated with memantine for 12 weeks. Factor analysis of the baseline ROSA total scores was performed based on the principal components method using the varimax orthogonal rotational procedure. The psychometric analyses of the ROSA included internal consistency, test-retest reliability, inter-rater reliability, construct validity, and responsiveness to changes over time. RESULTS: All items showed adequate factor loadings and were retained in the final ROSA as Factor 1 (all items related to cognition, communication, function, quality of life and caregiver burden) and Factor 2 (all behavior items). The ROSA demonstrated high internal consistency (Cronbach's α = 0.93), test-retest reliability (intraclass correlation coefficient = 0.93), and inter-rater reliability (intraclass correlation coefficient = 0.91). The correlation coefficients between the ROSA and each of the validated scales ranged between 0.4 and 0.7, confirming the ROSA construct validity. Nonsubstantial floor and ceiling effects were found in middle and late disease stages, whereas a small ceiling effect was observed in the early stage. The ROSA responsiveness to change was high (responsiveness index ≥0.8) for all severity stages. CONCLUSIONS: The ROSA is a valid and reliable instrument to aid medical practitioners in sensitively assessing AD-relevant symptoms over time in their clinical practice.

Canadian Alzheimer's disease caregiver survey: baby-boomer caregivers and burden of care.

OBJECTIVE: Alzheimer's disease (AD) burdens not only the person, but also the person's caregiver(s). This burden has been linked to negative health effects for caregivers. To that end, a survey of Canadian caregivers of persons with AD/other dementias was conducted to investigate the social, physical, psychological and financial impact of AD and/or dementia-related conditions on caregivers' quality of life. METHODS: A web-based survey, the Canadian Alzheimer's Disease Caregiver survey, was made available through the Canadian Alzheimer's Society website and 50plus.com, an internet portal for baby boomers (BB) (people aged 50 years or older), as well as through HarrisDecima Research's e-Vox panel. A total of 398 individuals completed the survey between 15 September and 5 November 2006. RESULTS: Of the 398 total respondents, 221 were identified as baby boomers who provided care to an individual with AD/dementia. Respondents identified several areas of burden of care. These included negative effects on emotional health (such as increased depression, more stress and greater fatigue), financial costs and a need to change a working situation (e.g. by retiring early, reducing work hours or refusing a promotion). CONCLUSION: Caregivers of persons with AD/related dementia face important social, physical, psychological and financial pressures. These negatively affect the quality of life of caregivers with a significant increased burden being placed on live-in caregivers versus caregivers who do not co-reside with their care recipients. Interventions that address these pressures will not only improve the health and well-being of caregivers, but likely also the care of persons with AD/dementia.

Severe Impairment Battery Language scale: a language-assessment tool for Alzheimer's disease patients.

BACKGROUND: Communication problems are common in Alzheimer's disease (AD) patients, but instruments to assess these symptoms are limited. Our objective was to create a new scale, based on the language subscale of the Severe Impairment Battery (SIB), as a sensitive and reliable measurement of treatment effects on language performance. METHODS: All 24 items of the SIB language subscale were chosen for analysis. Baseline scores of 1320 moderate-to-severe patients (Mini-Mental State Examination [MMSE] score, <15), from a combined AD database of four Memantine clinical trials (Study Codes: IE-2101, MEM-MD-01, MEM-MD-02, and MRZ-9605), were used for item reduction according to a standard principal components factor analysis. All items with loadings >0.5 on the identified factors were selected for inclusion in the new language scale. Correlations with existing AD scales were examined. RESULTS: The analysis indicated six factors, with 21 of 24 items showing loadings >0.5. The resulting 21-item SIB Language (SIB-L) scale exhibited high internal consistency (Cronbach's alpha = 0.809). The maximal SIB-L score was 41 points, with a measurement error of 3.7 points. The stratification of baseline SIB-L scores (mean, 31.7; SD, 8.4) by MMSE scores (mean, 9.7; SD, 3.3) showed a high variance in SIB-L scores. This confirms that patients with a low MMSE score can possess preserved language abilities. The SIB-L scale did not exhibit substantial floor-and-ceiling effects. CONCLUSIONS: The new SIB-L is a fast (<15 minutes) and easily administered scale with favorable psychometric characteristics for assessing language impairment and treatment effects on the language performance of patients with moderate to severe AD.

International price comparisons of Alzheimer's drugs: a way to close the affordability gap.

BACKGROUND: Alzheimer's drugs are believed to have limited availability and to be unaffordable in low- and middle-income countries compared to high-income countries. The price, availability and affordability of Alzheimer's drugs have not been reported before. METHODS: During 2007 an international survey was conducted in 21 countries in six continents (Argentina, Australia, Brazil, the Dominican Republic, France, India, Japan, Macedonia, Mexico, New Zealand, Nigeria, the Philippines, Portugal, Serbia, South Korea, Switzerland, Taiwan, Thailand, Uganda, the U.K. and the U.S.A.). Prices of Alzheimer's drugs were compared using the affordability index (the total number of units purchasable with one's daily income) derived from purchasing power parity (PPP) converted prices as well as raw prices. RESULTS: Donepezil is available in all 21 countries, whereas the newer drugs are less available. A 5 mg tablet of branded originator donepezil costs just US$0.26 in India and US$0.31 in Mexico, whereas it costs US$6.64 in the U.S.A. Pricing conditions of rivastigmine, galantamine and memantine appear to be similar to that of donepezil. The cheapest branded originators are from India and Mexico. However, in terms of PPP, Alzheimer's drugs in other low- and middle-income countries are much more expensive than in high-income countries. Most people in low- and middle-income countries cannot afford Alzheimer's drugs. CONCLUSIONS: Alzheimer's drugs, albeit available, are often unaffordable for those who need them most. It is hoped that equitable differential pricing will be applied to Alzheimer's drugs.

Impact of vascular risk factors and diseases on cognition in persons with mild cognitive impairment.

BACKGROUND/AIM: To investigate the impact of vascular burden (assessed by the number of vascular risk factors and diseases) on the cognition of persons with amnestic mild cognitive impairment (aMCI). METHODS: This study included 145 participants; 68 meeting criteria for amnesic single-domain or multiple-domain MCI and 77 matched controls. Four cognitive domains were assessed: executive functions, processing speed, episodic memory and general cognitive functioning. RESULTS: A larger vascular burden among aMCI is correlated with lower performance in the executive domain. In addition, persons with aMCI with high vascular burden were more frequently of the multiple domain subtype, whereas persons with no vascular burden were more frequently of the single domain subtype. CONCLUSION: Our findings suggest that the combined effect of multiple vascular risk factors and diseases increases the amount of executive impairment in persons with aMCI. Vascular burden may play an important role in the heterogeneity of aMCI by impairing cognitive functions other than memory.

A roadmap for the prevention of dementia II: Leon Thal Symposium 2008.

This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

The assessment of recognition memory using the Remember/Know procedure in amnestic mild cognitive impairment and probable Alzheimer's disease.

This study used the Remember/Know (R/K) procedure combined with signal detection analyses to assess recognition memory in 20 elders with amnestic mild cognitive impairment (aMCI), 10 patients with probable Alzheimer's disease (AD) as well as matched healthy older adults. Signal detection analyses first indicated that aMCI and control participants were comparable on general recognition performance. As regards AD patients, they were impaired relative to both aMCI and healthy elders. When assessing Remember and Know responses the aMCI group showed diminished sensitivity for Remember responses but intact Know responses compared to healthy elders. In contrast, AD patients showed decreased sensitivity for both Remember and Know responses compared to control and aMCI participants. The response bias index revealed that AD patients were more liberal than aMCI and control participants when providing Know responses. On the other measures, response bias was comparable between the groups. Overall, this study indicates that the R/K procedure can characterize different aspects of recognition memory performance in persons with aMCI or AD.