Decreasing incidence of stroke, ischaemic heart disease and dementia in Norway, 1990-2019, a Global Burden of Disease study: an opportunity.

BACKGROUND AND PURPOSE: The declining incidence of stroke, ischaemic heart disease (IHD) and dementia (the 'triple threat') in Norway encourages further investigation. The risks and trends of the three conditions were analysed using data from the Global Burden of Disease study. METHODS: Global Burden of Disease 2019 estimations were used for age-, sex- and risk-factor-specific incidence and prevalence of the 'triple threat', their risk-factor-attributed deaths and disability combined, their age-standardized rates per 100,000 population in 2019 and their changes during 1990-2019. Data are presented as means and 95% uncertainty intervals. RESULTS: In 2019, 71.1 thousand Norwegians were living with dementia, 157.2 thousand with IHD and 95.2 thousand with stroke. In 2019, there were 9.9 thousand (8.5 to 11.3) new cases of dementia (35.0% increase since 1990), 17.0 thousand (14.6 to 19.6) with IHD (3.6% decrease) and 8.0 thousand (7.0 to 9.1) with stroke (12.9% decrease) in Norway. During 1990-2019, their age-standardized incidence rates decreased significantly-dementia by -5.4% (-8.4% to -3.2%), IHD by -30.0% (-31.4% to -28.6%) and stroke by -35.3% (-38.3% to -32.2%). There were significant declines in the attributable risks to both environmental and behavioural factors in Norway, but contradictory trends for metabolic risk factors during 1990-2019. CONCLUSIONS: The risk of the 'triple threat' conditions is declining in Norway, despite the increased prevalence. This offers the opportunity to find out why and how and to accelerate their joint prevention through new approaches and the promotion of the National Brain Health Strategy.

Integral brain health: Cerebral/mental/social provisional definitions.

Brain health matters to everyone, we all need to know what it is. The digital age, the knowledge-based society, and expanding virtual worlds require greater cognitive capacity and mental and social resilience to function and to contribute; and yet there are no agreed definitions for brain, mental, or social health. Moreover, no definition encompasses all three or recognizes their integrated, interactive nature. Such a definition would: Help integrate relevant facts lingering behind specialized definitions and jargons. Promote a more holistic approach to patients. Create synergies among disciplines. The new definition would come in three versions: A lay, a scientific, and a customized one depending on the purpose, for example, research, education, policy, and so forth. Buttressed by evolving evidence integrated and update through a Brainpedia, they would focus attention on the greatest investment that individuals and society can make: Integral brain health: Cerebral/mental/social, in a safe, healthy, and supportive environment.

Global, regional, and national trends of dementia incidence and risk factors, 1990-2019: A Global Burden of Disease study.

BACKGROUND: An ample literature documents the growing prevalence of dementia and associated costs. Less attention has been paid to decreased dementia incidence in some countries. METHODS: We analyzed trends in age-standardized dementia, stroke, and ischemic heart disease (the triple threat) incidence rates and population attributable fraction of death and disability attributable to 12 risk factors in 204 countries and territories and 51 regions using Global Burden of Disease 2019 data. RESULTS: During 1990 to 2019, dementia incidence declined in 71 countries; 18 showed statistically significant declines, ranging from -12.1% (95% uncertainty intervals -16.9 to -6.8) to -2.4% (-4.6 to -0.5). During 2010 to 2019, 16 countries showed non-significant declines. Globally, the burden of the triple threat attributable to air pollution, dietary risks, non-optimal temperature, lead exposure, and tobacco use decreased from 1990 to 2019. CONCLUSION: The declining incidence of dementia in some countries, despite growing prevalence, is encouraging and urges further investigation.

Brain health and mental health: Common vascular risk factors and practical implications.

The pandemic dramatized the close links among cognitive, mental, and social health; a change in one reflects others. This realization offers the opportunity to bridge the artificial separation of brain and mental health, as brain disorders have behavioral consequences and behavioral disorders affect the brain. The leading causes of mortality and disability, namely stroke, heart disease, and dementia, share the same risk and protective factors. It is emerging that bipolar disorders, obsessive compulsive disorders, and some depressions share these risk factors, allowing their joint prevention through a holistic life span approach. We need to learn to focus on the whole patient, not simply on a dysfunctional organ or behavior to mitigate or prevent the major neurological and mental disorders by fostering an integrated approach to brain and mental health and addressing the common, treatable risk factors.

White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: A meta-analysis, systematic review, and recommendations for future study harmonization.

INTRODUCTION: The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological approaches, allowing researchers to design future studies targeting current knowledge gaps. METHODS: A meta-analysis and systematic review was performed investigating associations between baseline WMHs and longitudinal cognitive outcomes in cognitively normal populations, and populations with mild cognitive impairment (MCI), Alzheimer's disease (AD), and stroke. RESULTS: Baseline WMHs increase the risk of cognitive impairment and dementia across diagnostic categories and most consistently in MCI and post-stroke populations. Apolipoprotein E (APOE) genotype and domain-specific cognitive changes relating to strategic anatomical locations, such as frontal WMH and executive decline, represent important considerations. Meta-analysis reliability was assessed using multiple methods of estimation, and results suggest that heterogeneity in study design and reporting remains a significant barrier. DISCUSSION: Recommendations and future directions for study of WMHs are provided to improve cross-study comparison and translation of research into consistent clinical interpretation.

Intravenous Thrombolysis After First-Ever Ischemic Stroke and Reduced Incident Dementia Rate.

BACKGROUND: The use of intravenous thrombolysis is associated with improved clinical outcomes. Whether thrombolysis is associated with reduced incidence of poststroke dementia remains uncertain. We sought to estimate if the use of thrombolysis following first-ever ischemic stroke was associated with a reduced rate of incident dementia using a pragmatic observational design. METHODS: We included first-ever ischemic stroke patients from the Ontario Stroke Registry who had not previously been diagnosed with dementia. The primary outcome was incident dementia ascertained by a validated diagnostic algorithm. We employed inverse probability of treatment-weighted Cox proportional hazard models to estimate the cause-specific hazard ratio for the association of thrombolysis and incident dementia at 1 and 5 years following stroke. RESULTS: From July 2003 to March 2013, 7072 patients with ischemic stroke were included, 3276 (46.3%) were female and mean age was 71.0 (SD, 12.8) years. Overall, 38.2% of the cohort (n=2705) received thrombolysis, 77.2% (n=2087) of which was administered within 3 hours of stroke onset. In the first year following stroke, thrombolysis administration was associated with a 24% relative reduction in the rate of developing dementia (cause-specific hazard ratio, 0.76 [95% CI, 0.58-0.97]). This association remained significant at 5 years (cause-specific hazard ratio, 0.79 [95% CI, 0.66-0.91]) and at the end of follow-up (median 6.3 years; cause-specific hazard ratio, 0.79 [95% CI, 0.68-0.89]). CONCLUSIONS: Thrombolysis administration following first-ever ischemic stroke was independently associated with a reduced rate of dementia. Incident dementia should be considered as a relevant outcome when evaluating risk/benefit of thrombolysis in ischemic stroke patients.

From Dementia to Eumentia: A New Approach to Dementia Prevention.

BACKGROUND: During the past 40 years, dementia prevention approaches have ranged from searching for a drug to prevent progression to Alzheimer's disease to preventing dementia through multidomain lifestyle interventions. Current Approaches: The search for a silver bullet has yielded good science but no clinical results. The multi-model lifestyle intervention approach has shown encouraging results. The largest proportion of resources in prevention have been devoted to finding a drug to prevent, mitigate, or delay what is being called "Alzheimer's disease of late onset." The reality is that Alzheimer's pathology is common among the elderly, but it seldom only occurs alone. The only treatable and preventable pathology currently is vascular. Hence arose the concept of "vascular cognitive impairment" meaning any vascular cause or risk factor associated with cognitive impairment. The majority of cases of cognitive impairment in the elderly have a vascular component that is treatable and preventable and identifiable by several means, including a simple ischemic score. CONCLUSION: Since environmental, socioeconomic, and individual risk factors contribute to dementia, we proposed a Comprehensive, Customized, Cost-effective APProach (the CCC-APP) implemented in actionable units with the focus on promoting brain health (eumentia). KEY MESSAGES: We should implement dementia prevention approaches in actionable units around optimal brain health or eumentia. Heart disease, stroke, and dementia share mostly the same risk and protective factors; thus, their joint prevention is desirable. We need a comprehensive, customized, and cost-effective approach to joint prevention of stroke, heart disease, and dementia. We call for literal and virtual meetings of researchers of all the relevant disciplines to work on operational definitions and interdisciplinary collaborations.

Secular trends of ischaemic heart disease, stroke, and dementia in high-income countries from 1990 to 2017: the Global Burden of Disease Study 2017.

BACKGROUND: We assessed secular trends in the burden of ischaemic heart disease (IHD), stroke, and dementia in the Organization for Economic Co-operation and Development (OECD) countries. METHODS: Using the Global Burden of Disease (GBD) Study 2017, we compared sex-specific and age-standardized rates of disability-adjusted life years (DALY); mortality, incidence, and prevalence of IHD and stroke; and dementia per 100,000 people, in the world, OECD countries, and Canada. RESULTS: From 1990 to 2017, the crude incidence number of IHD, stroke, and dementia increased 52%, 76%, and 113%, respectively. Likewise, the prevalence of IHD (75%), stroke (95%), and dementia (119%) increased worldwide. In addition during the study period, the crude global number of deaths of IHD increased 52%, stroke by 41%, and dementia by 146% (9, 6, and 3 million deaths in 2017, respectively). Despite an increase in the crude number of these diseases, the global age-standardized incidence rate of IHD, stroke, and dementia decreased by -27%, - 11%, and - 5%, respectively. Moreover, there was a decline in their age-standardized DALY rates (- 1.17%, - 1.32%, and - 0.23% per year, respectively) and death rates (- 1.29%, - 1.46%, and - 0.17% per year, respectively), with sharper downward trends in Canada and OECD countries. Almost all trends flattened during the last decade. CONCLUSIONS: From 1990 to 2017, the age-standardized burden of IHD, stroke, and dementia decreased, more prominently in OECD countries than the world. However, their rising crude numbers mainly due to population growth and ageing require urgent identification of reversible risk and protective factors.

The comprehensive, customized, cost-effective approach (CCCAP) to prevention of dementia.

The Food and Drug Administration's controversial approval of aducanumab has sounded a wake-up call. Is the search of a silver bullet to stop Alzheimer's disease the only way to prevent dementia? The controversies and costs have opened minds to alternative approaches, the most promising being that we are already preventing some dementias in some high-income countries but do not know yet how. This article proposes one way. It requires that the approach be (1) comprehensive, taking into account all relevant environmental, socioeconomic, and individual risk and protective factors; (2) customized, because contributing factors vary by region and among individuals; and (3) cost effective, implemented in actionable units. Savings of scale could occur by preventing stroke, heart disease, and dementia together. They share the same risk factors and pose risks for each other. Brain health could be the unifying, motivating, and actionable key to health, productivity, and well-being.

We are preventing some dementias now-But how? The Potamkin lecture.

Most dementias are untreatable and their prevalence is increasing around the world. However, the incidence of dementia is declining in some countries. We need to find out urgently why and how and apply the lessons promptly and widely. Given the multiplicity and variability of environmental, socioeconomic, and individual risk and protective factors, the approach needs to be comprehensive, customized to work in a particular setting, and cost effective, to justify the needed funding. Stroke, heart disease, and dementia share the same major preventable risk and protective factors and pose risks for each other. Preventing them together might result in efficiencies and economies of scale. Prevention can best occur in existing actionable population health units through established leaders in government, non-governmental organizations, and the community, around a positive message of promoting brain health as the key to health, productivity, and well-being.

A new definition of brain reserve.

Brain reserve definitions foster debate and disagreements. A consensus definition of brain reserve would fill gaps in converging ongoing research and action plans to promote brain health. Different terms are used for the capacity to adapt to life hardships and cognitive and social compliance and to neutralize or compensate for age-related neurological degeneration to prevent impaired cognition. Brain reserve, resilience, cognitive reserve, and brain maintenance have been used usually in isolation, but at times interchangeably. However, the need remains for a simplified overarching definition of brain reserve. Brain health is a continuous development and exercise of the brain, and thus the brain reserve requires a definition encompassing this continuum. We propose for discussion a new definition of brain reserve that incorporates available definitions and emphasizes the dynamic and interactive nature of a healthy brain. Brain reserve is the lifelong, dynamic, interactive, accumulating capacity to resist physical, emotional, and/or social harms.

Brain health: Key to health, productivity, and well-being.

Brain health is essential for physical and mental health, social well-being, productivity, and creativity. Current neurological research focuses mainly on treating a diseased brain and preventing further deterioration rather than on developing and maintaining brain health. The pandemic has forced a shift toward virtual working environments that accelerated opportunities for transdisciplinary collaboration for fostering brain health among neurologists, psychiatrists, psychologists, neuro and socio-behavioral scientists, scholars in arts and humanities, policymakers, and citizens. This could shed light on the interconnectedness of physical, mental, environmental, and socioeconomic determinants of brain disease and health. We advocate making brain health the top priority worldwide, developing common measures and definitions to enhance research and policy, and finding the cause of the decline of incidence of stroke and dementia in some countries and then applying comprehensive customized cost-effective prevention solutions in actionable implementation units. Life cycle brain health offers the best single individual, communal, and global investment.

The apathy, gait impairment, and executive dysfunction (AGED) triad vascular variant.

Apathy, gait disturbances, and executive dysfunction (AGED) often occur together. Although they can arise independently, the presence of one might portend another. This recognition suggests the possible etiology. We focus on the most common, the vascular. We explain the AGED vascular mechanism through the ambibaric brain concept. The brain contains two complementary blood pressure systems: One high in the primitive brain (brainstem, basal ganglia, and thalamus) and a low-pressure system in the Homo sapiens brain (cerebral hemispheres). Hypertension inflicts the most damage on the primitive brain. The frontal systems connect to the basal ganglia, then the thalamus and back to the cortex. Many connections converge on the primitive brain where they are damaged by vascular disease. We need methods of determining optimal, individual blood pressures. Although the AGED triad can result from other causes, it should first signal a vascular etiology, the most prevalent, treatable, and preventable one.

The Ambibaric Brain: Pathophysiological and Clinical Implications.

We propose a new evolutionary interpretation of the brain's circulation that has physiological, pathophysiological, and clinical implications. We review the evidence for the concept, discuss clinical implications, and suggest techniques to address outstanding questions. We conclude that the brain circulation contains complementary low-pressure and high-pressure system that must be kept in balance for optimal brain health.

Stroke and dementia, leading causes of neurological disability and death, potential for prevention.

INTRODUCTION: Stroke and dementia share a number of modifiable risk factors and are the leading cause of neurological disability and death worldwide. METHODS: We report the 2019 estimations for global disability-adjusted life years (DALYs) and death numbers and rates related to stroke and dementia, as well as their risk attributed DALYs and deaths and their changes between 2010 and 2019. RESULTS: Stroke accounted for 69.8%, dementia for 17.3%, and combined contributed to 87.2% (8.2 million) of neurological deaths and 61.7% (168.5 million) of neurological DALYs in 2019. For stroke, 86.4% of DALYs and for dementias 32.8% of DALYs are attributable to risk factors. Globally, hypertension (54.8%) and unhealthy diet (30.0%) pose the greatest risk for stroke DALYs, and smoking (15.1%) and obesity (12.5%) for dementia DALYs. DISCUSSION: Worldwide, stroke and dementia cases are increasing in number, but their age-standardized rates are falling. Finding out why offers the possibility of their joint delay, mitigation, or prevention.

Dual decline in gait speed and cognition is associated with future dementia: evidence for a phenotype.

BACKGROUND: concurrent declines in gait speed and cognition have been associated with future dementia. However, the clinical profile of 'dual decliners', those with concomitant decline in both gait speed and cognition, has not been yet described. We aimed to describe the phenotype and the risk for incident dementia of those who present with dual decline in comparison with non-dual decliners. METHODS: prospective cohort of community-dwelling older adults free of dementia at baseline. We evaluated participants' gait speed, cognition, medical status, functionality, incidence of adverse events and dementia, biannually over 7 years. Gait speed was assessed with a 6-m electronic walkway and global cognition using the MoCA test. We compared characteristics between dual decliners and non-dual decliners using t-test, chi-square and hierarchical regression models. We estimated incident dementia using Cox models. RESULTS: among 144 participants (mean age 74.23 ± 6.72 years, 54% women), 17% progressed to dementia. Dual decliners had a 3-fold risk (HR: 3.12, 95%CI: 1.23-7.93, P = 0.017) of progression to dementia compared with non-dual decliners. Dual decliners were significantly older with a higher prevalence of hypertension and dyslipidemia (P = 0.002). Hierarchical regression models show that age and sex alone explained 3% of the variation in the dual decliners group. Adding hypertension and dyslipidemia increased the explained variation by 8 and 10%, respectively. The risk of becoming a dual decliner was 4-fold higher if hypertension was present. CONCLUSION: older adults with a concurrent decline in gait speed and cognition represent a group at the highest risk of progression to dementia. Older adults with dual decline have a distinct phenotype with a higher prevalence of hypertension, a treatable condition.

No difference in dementia prediction between apolipoprotein E4 and the ischemic score.

INTRODUCTION: Few biomarkers exist for early detection of vascular cognitive impairment. We examined whether the Hachinski Ischemic Scale (HIS) can predict dementia in elderly. METHODS: We leveraged data of the Canadian Study of Health and Aging. First, we examined the association of HIS with incident dementia. Next, we compared HIS to apolipoprotein E (APOE ɛ4) in prediction of dementia. We trained the HIS and APOE ɛ4 models in the training dataset and used the trained models for dementia prediction in the validation dataset. RESULTS: A higher HIS level was associated with a higher odds of dementia (odds ratio = 1.64, 95% confidence interval [CI]: 1.41 to 1.90, P < .001). Dementia discrimination of the HIS model was not different from the APOE ɛ4 model (area under the curve difference = 0.002, 95% CI: -0.024 to 0.029, P = .857). The calibration of the HIS model was 13.7 (P = .091) and of the APOE ɛ4 model was 13.3 (P = .100). DISCUSSION: HIS may be used as a simple, inexpensive test to identify older adults at risk of developing dementia.

Impaired behavioural flexibility related to white matter microgliosis in the TgAPP21 rat model of Alzheimer disease.

Executive dysfunction and white matter inflammation continue to be relatively understudied in rodent models of Alzheimer's disease (AD). Behavioural inflexibility is an important component of executive dysfunction that can be further categorized as perseverative or regressive, which respectively specify whether maladaptive persistence occurs early or late during a behavioural change. Previous studies of the TgAPP21 rat model of AD (expressing pathogenic hAPP) suggested a potentially spontaneous increase of regressive behavioral inflexibility. In this study, 7-8-month-old male TgAPP21 rats were tested for behavioral flexibility, learning, and memory using an operant conditioning chamber and the Morris Water Maze (MWM). TgAPP21 rats demonstrated a regressive behavioral inflexibility during set shifting in an operant conditioning chamber (regressive errors η2 = 0.32 and number of errors after criterion η2 = 0.33). Regressive behavior was also demonstrated in the MWM probe test, wherein TgAPP21 rats significantly increased their swim time in the target quadrant during the last third of the probe test (43% vs 33% in the first 2 thirds of the probe test or the Wt rats' 29%-32%); this behavioral phenotype has not been previously described in the MWM. TgAPP21 demonstrated further impairment of behavioural inflexibility as they committed a greater number of reversal errors in the operant conditioning chamber (η2 = 0.30). Diffuse microglia activation was increased in the white matter tracts of TgAPP21 (corpus callosum, cingulum, and internal capsule; η2 = 0.59-0.62), which was found to correlate with the number of reversal errors in the operant conditioning chamber (R2 = 0.42). As TgAPP21 rats do not spontaneously develop amyloid plaques but have been shown in previous studies to be vulnerable to the development of plaques, these rats demonstrate an important onset of cognitive change and inflammation in the pre-plaque phase of AD. TgAPP21 rats are also an instrumental model for studying the role and mechanism of white matter microglial activation in executive functioning. This is pertinent to clinical research of prodromal AD which has suggested that white matter inflammation may underlie impairment of executive functions such as behavioral flexibility.

Evidence of Concomitantly Increasing Stroke and Dementia Prevalence among those 80 Years and Older in Ontario, Canada, 2003-04 to 2012-13.

Among those aged 80 years and older in Ontario, Canada, stroke and dementia incidence declined concomitantly from 2002-03 to 2013-14. This study aimed to report the concurrent temporal trends of stroke and dementia prevalence in Ontario among the same age demographic. The prevalence of both stroke and dementia increased from 2003-04 to 2012-13 in both sexes and the magnitude in which prevalence of dementia increased over time exceeded that of stroke. The substantial increase in the prevalence of dementia may be because of increased recognition and diagnoses of dementia and increased survival of stroke patients who are at higher risk of developing dementia.

Des preuves quant à une augmentation simultanée de la prévalence des AVC et de la démence. De 2002-2003 à 2013-2014, on a noté une diminution simultanée de l'incidence des AVC et de la démence parmi les individus âgés de plus de 80 ans vivant en Ontario (Canada). Ce qui nous intéresse dans cette étude, ce sont les tendances temporelles simultanées en ce qui a trait à la prévalence des AVC et de la démence au sein de la même tranche d'âge et dans la même province. On a ainsi noté que tant la prévalence des AVC que celle de la démence ont augmenté entre 2003­2004 et 2012­2013, et ce, tant chez les hommes que chez les femmes. Cela dit, l'ampleur de l'augmentation de la prévalence de la démence a fini par dépasser au fil du temps celle des AVC. Il se pourrait que l'augmentation substantielle de la prévalence des cas de démence puisse être attribuée à un dépistage accru et à l'établissement de plus nombreux diagnostics ainsi qu'à un accroissement de la survie des patients victimes d'AVC, ces derniers étant alors plus susceptibles d'être atteints de démence.

Dementia: new vistas and opportunities.

Over the past four decades, Alzheimer disease has become near synonymous with dementia and the amyloid/tau hypothesis as its dominant explanation. However, this monorail approach to etiology has failed to yield a single disease-modifying drug. Part of the explanation stems from the fact that most dementias in the elderly result from interactive Alzheimer and cerebrovascular pathologies. Stroke and dementia share the same risk factors and their control is associated with a decrease in stroke and some dementias. Additionally, intensive control of risk factors and enhancement of protective factors improve cognition. Moreover, anticoagulation of atrial fibrillation patients decreases their chance of developing dementia by 48%. Preliminary data suggest that treating blood pressure to a target of 120 mmHg systolic compared to a target of 140 mmHg decreases the chances of mild cognitive impairment by 19%. The Berlin Manifesto establishes the scientific bases of "preventing dementia by preventing stroke." Enlarging our vista of dementia to include cerebrovascular disease offers the opportunity of preventing not only stroke, but some dementias, beginning now.