Regulatory issues in vascular dementia: a European perspective

In many studies vascular dementia (VaD) is the second most frequent cause of organic acquired cognitive dysfunction; accounting for 10% to 50% of the cases, depending on the geographical area, patient population, and diagnostic criteria used. There is growing evidence that VaD does not include only multi-infarct dementia (MID) but relates to complex interactions of different etiologies (risk factors, cerebrovascular disease), structural changes in the brain, host factors and cognition. This resulted in reconceptualization of VaD to emphasize the differences from Alzheimer's disease (AD). However, the diagnostic criteria used (DSM-IV, ICD-10, NINDS-AIREN, or ADDTC) are based on the experience with AD and as such have their limitations and are not interchangeable. From a regulatory point of view, therefore, future research is needed to better define VaD in general and possible subtypes of VaD as targets for drug trials. Methodological issues in VaD trials, as opposed to AD, will be emphasized. The European Medicinal Products Evaluation Agency (EMEA) has adopted a guideline for trials of symptomatic treatments of dementia, particularly in AD. There is no explicit guideline for VaD trials; however, many of the recommendations for AD are already applicable to VaD for drugs aiming at alleviating symptoms of dementia. On the other hand, VaD may be potentially preventable, underscoring the importance of primary and secondary prevention as in other cerebrovascular disorders. Large long-term trials are necessary to study the importance of different risk factors and possible intervention strategies with special reference to VaD.     

Outcome measures in clinical trials on medicinal products for the treatment of dementia: a European regulatory perspective

Based on efficacy and safety data, several drugs have been approved for symptomatic improvement of dementia of the Alzheimer type and one for the symptomatic improvement of dementia associated with Parkinson's disease. However, established treatment effects must be considered as modest. Randomized clinical trials in other subtypes of dementia (e.g. vascular dementia) have not been able to demonstrate clinically relevant symptomatic improvement, nor has it yet been possible to establish disease-modifying effects in any dementia syndrome or its subtypes. Recent progress in basic science and molecular biology of the dementias has now fostered new interest for more efficacious symptomatic treatments as well as for disease-modifying approaches in the degenerative dementias. For regulatory purposes this requires better standardization and refinement of diagnostic criteria, which allow the study of homogeneous disease populations in specialized academic centers as well as in the general community setting. Depending on the disease stages (early versus late, mild to moderate to severe impairment) and disease entities, distinct assessment tools for cognitive, functional and global endpoints should be used or newly developed. The typical design to show symptomatic improvement is a randomized, double-blind, placebo-controlled, parallel group study comparing change in two primary endpoints, one of them reflecting the cognitive domain and the second preferably reflecting the functional domain of impairment. The changes must be robust and clinically meaningful in favor of active treatment versus placebo. If a treatment claim for prevention of the emergence, slowing or stabilizing deterioration is strived for, it has to be shown that the treatment has an impact on the underlying neurobiology and pathophysiology of the process of dementia. Establishing such an effect in a highly variable progressing syndrome is complex and difficult; however, a variety of trial designs has been provided, including baseline designs, survival designs, randomized start or randomized withdrawal designs, with or without incorporation of biomarkers as surrogate endpoints (e.g. magnetic resonance tomography, emission tomography, cerebrospinal fluid markers). To be accepted as a surrogate endpoint such a biomarker ideally should respond to treatment, predict clinical response and be compellingly related to the pathophysiological process of the dementia. However, careful and sufficient validation of proposed biomarkers as a potential surrogate endpoint is a prerequisite for acceptance by regulatory bodies. This review outlines the regulatory requirements for approval of a new medicinal product for symptomatic improvement or disease-modifying effects in patients with dementia, with special emphasis on the importance of validation of the assessment tools and potential surrogate endpoints based on recent experience and discussion regarding anti-dementia drugs in the European framework.     

Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group

OBJECTIVE: To study the difference in risk for dementing diseases between men and women. BACKGROUND: Previous studies suggest women have a higher risk for dementia than men. However, these studies include small sample sizes, particularly in the older age groups, when the incidence of dementia is highest. METHODS: Pooled analysis of four population-based prospective cohort studies was performed. The sample included persons 65 years and older, 528 incident cases of dementia, and 28,768 person-years of follow-up. Incident cases were identified in a two-stage procedure in which the total cohort was screened for cognitive impairment, and screen positives underwent detailed diagnostic assessment. Dementia and main subtypes of AD and vascular dementia were diagnosed according to internationally accepted guidelines. Sex- and age-specific incidence rates, and relative and cumulative risks for total dementia, AD, and vascular dementia were calculated using log linear analysis and Poisson regression. RESULTS: There were significant gender differences in the incidence of AD after age 85 years. At 90 years of age, the rate was 81.7 (95% CI, 63.8 to 104.7) in women and 24.0 (95% CI, 10.3 to 55.6) in men. There were no gender differences in rates or risk for vascular dementia. The cumulative risk for 65-year-old women to develop AD at the age of 95 years was 0.22 compared with 0.09 for men. The cumulative risk for developing vascular dementia at the age of 95 years was similar for men and women (0.04). CONCLUSION: Compared with men, women have an increased risk for AD. There are no gender differences in risk for vascular dementia.     

Vascular dementia: European perspectives

Vascular dementia (VaD) is the second most frequent cause of organic acquired cognitive dysfunction in the Western world and is probably the first cause in some Asian countries. Therefore, it represents an important target for drug trials in dementia. This report puts in perspective methodological issues in VaD trials, as opposed to Alzheimer disease (AD), and reproduces in extenso the European Medicinal Products Evaluation Agency (EMEA) guidelines for trials of symptomatic treatments of dementia, particularly in AD. There are no explicit guidelines for VaD trials, but many of the recommendations for AD are already applicable to VaD for drugs aiming at alleviating symptoms of dementia. However, VaD can be viewed as being one of the many possible consequences of cerebrovascular diseases, so that there is more to expect from secondary prevention strategies for VaD than for AD (in which both the etiology and the pathophysiological mechanisms are largely unknown). So it seems logical to put more emphasis on the stabilization of the symptoms of VaD, by preventing progression or recurrence insofar as the vascular risk factors for VaD can often be identified and controlled, than in attempting to improve the existing clinical manifestations of established vascular brain damage. Even if purely symptomatic drugs are developed to improve the symptoms of VaD, they will have to be studied in the context of a tight control of existing vascular risk factors. For secondary prevention, trials of at least 1 year seem advisable.     

Vascular dementia: the Latin American perspective

Population aging is a process that is especially accelerated in some parts of the world. One example is in Latin America. As with other developing regions, Latin America has to confront population "graying" in the context of an emerging economy. As a result of this and of their health history, the prevalence and incidence of age-related pathologies are different than those in the developed world. The burden of dementia is significant for patients, families, health systems, and public health. The aim of this paper was to summarize data from the scarce dementia epidemiological studies available in Latin America, the diagnostic criteria used in most countries and the most widely used diagnostic tools and neuropsychological assessment instruments (some of them translated, validated, and harmonized). Reference is made to the approval process and availability in Argentina of dementia and cognitive decline-related drugs.     

Vascular dementia: an Australian perspective

We performed a review of the published literature on dementia, stroke, and vascular dementia (VaD) emanating from Australia and sought the opinions of senior clinicians and investigators in the field of dementia. We conclude from these sources that the public health importance of cognitive impairment and dementia secondary to cerebrovascular disease is recognized in Australia as is the potential to alter the public health burden significantly by preventative strategies. VaD is considered to be a heterogenous group of syndromes, and there is a lack of consensus on the appropriate diagnostic criteria. The concept is considered to be in evolution and empirical support is needed for its definition, subtyping, and the understanding of the pathophysiological mechanisms. An alternative term--vascular cognitive disorder--is suggested to overcome some of the difficulties inherent in the concept of "dementia" as used currently. The importance of noncognitive disorders of vascular origin is highlighted. No treatment is recognized to be specifically effective in VaD. Australian clinicians and researchers are beginning to grapple with the many difficulties entailed in our understanding of the cognitive and noncognitive consequences of cerebrovascular disease. There is a need for an international consensus on diagnostic criteria, particularly for drug development and research.     

Executive cognitive impairment: a novel perspective on dementia

In 1994 the American Psychiatric Association added impairment of executive control functions (ECF) to its list of cognitive domains that should be considered in the assessment of dementia. This recommendation has not been widely implemented. None the less, there is growing evidence that ECF impairment is common, strongly associated with disability and functional decline, and not well detected by traditional dementia screening tests. This article reviews the implications of ECF for the epidemiology of dementia. The total number of dementia cases may be much greater than previously thought and we are likely to be selectively missing cases with reversible causes of ECF impairment.     

Lucidity in dementia: A perspective from the NIA

In this issue of Alzheimer's & Dementia, Mashour et al. propose the intriguing hypothesis that some manifestations of late-stage dementia are reversible, albeit transiently. Calling this phenomenon paradoxical lucidity, their paper follows a 2018 workshop sponsored by the National Institute on Aging that assessed the state of knowledge on lucidity in dementia and identified areas ripe for further study. The National Institute on Aging has since released two funding opportunity announcements (RFA-AG-20-016 and RFA-AG-20-017) to establish the building blocks of such a research program. The potential challenges of conducting such studies are matched by the potential opportunities to open a novel window onto our understanding of dementia. Initial findings from this research may eventually lead to studies that uncover novel mechanisms underlying cognitive decline, identify potential preventive or therapeutic approaches for individuals with dementia, offer more effective strategies for caregivers, and perhaps even expand our understanding of the nature of personhood and consciousness.     

Uncommon dementia and the carer's perspective

There is much caregiving literature describing factors that affect carer burden, and interventions that may be useful for carers of those with common dementias such as Alzheimer's disease (AD). By contrast, relatively little information and few data are available on potentially diverse issues facing carers of those with uncommon dementias, such as frontotemporal dementia (FTD), Huntington's disease (HD) and human immunodeficiency virus (HIV) dementia. This paper highlights particular characteristics of caregiving for those with uncommon dementias, and the unique needs that may arise for this group of carers who often "fall between the net" of services and supports available. Further research into this area is required.     

The anthropology of dementia: a narrative perspective

This article draws on recent thinking in the field of narrative gerontology to lend support to Mahnaz Hashmi's “anthropological perspective” on dementia. From a narrative perspective, the relational component of human life ‐ and thus of dementia ‐ is underscored. Moreover, when the narrative dimensions of memory are considered, the line between “normal” and “pathological” is revealed as finer than commonly assumed. Copyright © 2009 John Wiley & Sons, Ltd.     

Body mass index and incidence of dementia: the PAQUID study

To study the relationship between body mass index (BMI) and risk of dementia, a cohort of 3,646 individuals aged > or =65 years living at home and without cognitive disorders at baseline were followed up for 8 years (the PAQUID [Personnes Agées Quid] Study). Subjects with a BMI < 21 had an increased risk of developing dementia as compared with subjects whose BMI was between 23 and 26 (odds ratio = 1.48, 95% CI = 1.08 to 2.04). However, when individuals who developed dementia early during the follow-up were excluded from the analysis, this relationship was no longer significant. A low BMI does not in itself seem to be a risk factor for dementia.     

The incidence of dementia in an Australian community population: the Sydney Older Persons Study.

OBJECTIVES: Limited Australian dementia incidence data are available. This study aimed to identify the incidence of dementia and its subtypes in an Australian community dwelling population. METHOD: A community dwelling sample of 647 subjects aged > or =75 years at recruitment were followed for a mean period of 3.2 years (range 2.6-4.5 years). The incidence of dementia (measured in person years at risk) was identified for different levels of severity of dementia, Alzheimer's disease and vascular dementia. RESULTS: Incidence figures were slightly higher than those previously reported. The incidence of dementia and of Alzheimer's disease increased with age but was not affected by gender. The incidence of vascular dementia was not affected by age. CONCLUSION: This study provides the largest body of data on the incidence of dementia in Australia, indicating a slightly higher incidence of dementia than previous reports. Further Australian data are required to confirm these findings.