Preventing dementia by preventing stroke: The Berlin Manifesto

Abstract

The incidence of stroke and dementia are diverging across the world, rising for those in low- and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action.

Keywords: Alzheimer's disease; Cognitive impairment; Dementia; Neurovascular unit; Policy; Prevention; Resilience; Risk factor reduction; Stroke; Treatment.

Fig. 1.

Logos of the endorsing organizations [17].

Fig. 2.

Results from population-based studies on incidence trends: Hazard ratio and incidence rate ratio from five different studies from across the world [11].

Fig. 3.

Hypothetical updated Jack model of Alzheimer’s disease biomarkers to include the role of brain vasculature. Hypothetical model of AD biomarker changes illustrating that early cerebral blood flow and blood-brain barrier biomarkers and vascular dysfunction may contribute to initial stages of AD pathophysiological progression from NCI to MCI to AD, which is followed by cerebrospinal fluid and brain changes in Aβ and amyloid, and tau biomarkers. All biomarker curves converge at the top right-hand corner of the plot, that is, the point of maximum abnormality. The horizontal axis of disease progression is expressed as time. Cognitive response is illustrated as a zone (blue filled area) with low- and high-risk borders. Subjects with high risk of AD-related cognitive impairment are shown with a cognitive response curve that is shifted to the left. In contrast, the cognitive response curve is shifted to the right in subjects with a protective genetic profile, high cognitive reserve, and the absence of comorbid brain pathologies [31]. Abbreviations: AD, Alzheimer’s disease; CBF, cerebral blood flow; BBB, blood-brain barrier; MCI, mild cognitive impairment; NCI, no cognitive impairment.

Fig. 4.

Blood-brain barrier–mediated neurodegeneration [32].

Fig. 5.

Illustrates the graphic “simulation” of a hypothesis yet to be validated. This to be tested theory asserts that a large increase in the cytosol calcium ion concentration [Ca²⁺] I during a short period (e.g., 60–90 seconds) will trigger the same or similar sequence of molecular events that lead to neuronal dysfunction (e.g., “ischemic cascade”), as a smaller increase in [Ca²⁺] I, that is, sustained over a longer period (e.g., years); beyond the normal fluctuations around homeostatic zone [37]. The formula that summarizes this hypothetical relation is: $$\left\{\text{Large}\Delta \Uparrow {\left[{\text{Ca}}^{2+}\right]}_{\text{I}}\right\}/\{\text{Small}\Delta \text{T}\}\cong \left\{\text{Small}\Delta \Uparrow {\left[{\text{Ca}}^{2+}\right]}_{\text{I}}\right\}/\{\text{Large}\Delta \text{T}\}$$

Fig. 6.

Synergistic interaction between vascular risk factors and AD pathology: Vascular risk factors promote Aβ and tau accumulation by enhancing their production and reducing vascular clearance. In turn, AD pathology induces neurovascular dysregulation which aggravates the deleterious impact of vascular risk factors. Abbreviation: AD, Alzheimer’s disease.

Fig. 7.

Capillary function can be estimated by dynamic susceptibility contrast MRI. Blood mean transit time, a traditional marker of cerebral perfusion, is supplemented with the standard deviation of blood transit times within each image voxel. The ratio of the two, dubbed relative transit-time heterogeneity is taken as an index of the microvasculature’s ability to maintain uniform perfusion. The figure shows parametric RTH maps in patients with AD and healthy controls of similar age. Note how RTH tends to be elevated in AD patients compared with controls, suggesting that capillary flow homogenization is impaired in these patients [107]. Abbreviations: AD, Alzheimer’s disease; RTH, relative transit-time heterogeneity; MMSE, Mini Mental State Examination.

Fig. 8.

Risk of dementia with and without oral anticoagulation treatment at baseline (“intention to treat”). Multivariable Cox regression on propensity score matched cohorts [14]. Abbreviations: AF, atrial fibrillation; CI, confidence interval; HR, hazard ratio; NOAC, non-Vitamin K oral anticoagulant; VKA, Vitamin K antagonist.

Fig. 9.

The age-standardized prevalence rate of dementia in Canada is 6.8%; however, there is variation across provincial and territorial boundaries across Canada [125]. Abbreviations: BC, British Columbia; Alta, Alberta; Sask, Saskatchewan; Man, Manitoba; Ont, Ontario; Que, Quebec; NB, New Brunswick; NS, Nova Scotia; PEI, Prince Edward Island; NL, Newfoundland.