Oxford University Press, 2015

By Murray Grossman, MD

Neuroimaging is an important adjunct to clinical neurology. We cannot easily examine the brain directly. The neurologic exam is designed to allow us to make reasonable inferences about abnormalities of neurologic functioning, and neuroimaging helps us visualize the brain. This significantly enhances our ability as clinicians to diagnose the cause of a neurological abnormality and monitor response to an intervention. This is particularly true in neurodegenerative diseases, where the neurologic exam has been immensely assisted by neuroimaging. Indeed, with advances in neuroscientific knowledge, novel imaging techniques have been developed to provide additional insights into neurological functioning in health and disease.

Prof. Luca Saba has edited a comprehensive textbook Imaging in Neurodegenerative Disorders (Oxford University Press, 2015, 562 pages including an index). As the title indicates, this volume focuses on neurodegenerative diseases. While neurodegeneration has been an elusive domain of neurology, recent advances in imaging have contributed importantly to advancing clinical and scientific knowledge in this area.

The book consists of 10 sections. The introduction focuses on specific background knowledge areas, such as epidemiology, health economic considerations and molecular biology. A lengthy chapter is devoted to symptoms associated with neurodegenerative diseases, and readers might have found it easier to have portions of this chapter included in sections devoted to imaging of patients with the corresponding conditions.

Imaging techniques are presented in section two, which chapters devoted to computed tomography, magnetic resonance imaging, nuclear medicine and positron emission tomography. Although recent advances in techniques related to positron emission tomography are discussed, it is unfortunate that there is not an equivalent chapter on advances related to magnetic resonance imaging.

The heart of the text is in the subsequent seven sections. Each is devoted to a specific domain within neurodegeneration. Two large sections are devoted to disorders of cognition and movement disorders. The Cognition Section includes chapters on Alzheimer’s disease and an authoritative chapter on frontotemporal dementia by Jennifer Whitwell.

The Movement Section includes chapters considering Parkinson’s and Huntington’s diseases. This area of neurology is undergoing an important revolution. As treatments emerge for the underlying histopathologic abnormalities, classification based on phenotype gradually is giving way to classification based on targets of treatment, namely, pathology.

Phenotype-based classification has resulted in the inclusion of the chapters considering dementia with Lewy bodies and corticobasal syndrome in the Cognition Section, while conditions caused by similar histopathologic abnormalities, such as progressive supranuclear palsy (a tauopathy) and multisystem atrophy (a synucleinopathy), are placed in the Movement Section.

The section on strength contains a single authoritative chapter by Martin Turner, who considers imaging in amyotrophic lateral sclerosis. A considerable portion of this chapter is devoted to extramotor brain involvement. This appropriately acknowledges that up to half of patients with amyotrophic lateral sclerosis have cognitive deficits, and suggests that the title of the section might be adjusted.

Additional sections include chapters discussing coordination, demyelinating disorders, trauma and the peripheral nervous system. The final section is devoted to neuroimaging after therapy. This is a crucial consideration as therapies emerge for neurodegenerative diseases. It might have been useful here to consider quantitative measurement in neuroimaging since many of these techniques are being used as endpoints in treatment trials.

Imaging in Neurodegenerative Disorders is a comprehensive text that has an appropriately broad scope. Chapters are devoted to all the key areas in neurodegeneration, and the chapters are comprehensive. The book is generally well illustrated, although occasional images seem to have lower resolution than is needed to illustrate a finding optimally. I recommend this text to students of neurodegeneration who are interested in a comprehensive introduction to neuroimaging.

By Sarah Song, MD, MPH

Sarah Song

Stroke is a devastating and debilitating disease. It is the second leading cause of death in the world, comprising approximately 10 percent of all deaths and killing 5.5 million people each year, with 44 million disability-adjusted life-years (DALYs) lost.^1,2 In 2010 alone, there were 16.9 million strokes worldwide, of which 70 percent occurred in low- and middle-income countries; this trend is expected to increase over the next 20 years.^1,3

Presently, low- and middle-income countries account for more than 85 percent of the global stroke mortality.⁴ Stroke mortality rates are especially high in Africa and Asia, where the burden of preventing and treating communicable diseases may shift resources away from cardiovascular disease and stroke.⁵ However, the burden from chronic and non-communicable diseases is likely to exceed the burden from communicable diseases in low- and middle-income countries in the near future.

A global focus on reducing mortality and morbidity from cardiovascular disease and stroke is more urgent than ever. Major problems shared by many countries are a lack of infrastructure, inadequate systems of care, effective programs to address cardiovascular risk factors, financial difficulty and shortage of trained health care workers.^3,6 Advocacy efforts, partnerships between countries, efficient and cost-effective targeted interventions and allocated funding and resources are necessary to tackle the worldwide stroke burden.

Stroke began to be tracked globally via surveillance systems in 1968 with the World Health Assembly, after which data including incidence, mortality and case-fatality was tracked. In more recent years, a more sophisticated stepwise approach to stroke surveillance has been recommended by the World Health Organization to include not only individuals with non-fatal events in the community, but also those admitted to the hospital.

Stroke risk factors are also tracked using a stepwise surveillance approach, including demographic and self-reported data, physical examination and objective laboratory results.¹ These measures have helped to show the great disparity between low- and middle-income countries and high-income countries, with national per capita income being the highest predictor of stroke burden, exclusive of cardiovascular risk factors.⁷

Overall, between the countries with the highest stroke mortality and the lowest stroke mortality, a tenfold difference in age-adjusted mortality rates and DALYs lost was observed.⁷ Globally, the highest at-risk countries are in Eastern Europe (with Russia having the highest stroke mortality rate), Asia and Africa, along with some in the South Pacific and the Carribbean.⁷

The economic impact of stroke has also been severe. For example, in 2005 it was estimated that the losses to gross domestic product due to vascular diseases was nearly $1 billion in China and India. This economic disparity is expected to increase in the near future in low- and middle-income countries.¹

Health systems of care for stroke require financing, staffing and structure in order to produce results. For example, the administration of intravenous alteplase (IV tPA) has been seen to significantly improve outcomes after acute ischemic stroke. However, giving IV tPA appropriately to eligible patients requires infrastructure and organization. Several countries have successfully developed systems to administer IV tPA (e.g., Brazil, Argentina, China and India), but there are still many barriers in low-income countries where medical services may be scarce and not easily accessible due to geography or human resources, and IV tPA may be prohibitively expensive.

In addition, funding is not proportional to economic and patient burden. For example, in 2011, funding for three of the major infectious diseases (HIV/AIDS, tuberculosis and malaria) was 35 times greater than funding for all non-communicable conditions combined.³ Therefore, besides the need for much greater funding in the realm of stroke and cardiovascular diseases, it has been suggested that community interventions and a focus on primary care might be the most cost-effective and efficient approach to stroke on a global level.^3,6,7

Although stroke burden is significant regardless of cardiovascular risk factor burden, the overall risk factor burden is increasing in low- and middle-income countries.⁶ For instance, hypertension is held accountable for approximately 54 percent of global stroke burden; this could be especially important as a target for intervention in countries such as China, where rates of hypertension are increasing.¹ As many of the population in low- and middle-income countries with stroke are working age (41-65) adults, more smoking has been seen in working-age adults than in other age groups.

The obesity epidemic continues to rise (with an estimated 10 percent of children globally considered overweight). The three-year INTERSTROKE study, based in 84 centers in 22 countries, confirmed that 88 percent of strokes were attributable to 10 risk factors: hypertension, smoking, waist-to-hip ratio, diet risk score, physical activity, diabetes mellitus, alcohol intake, psychosocial factors (including depression and stress), cardiac causes and the ratio of apolipoprotein B to apolipoprotein A1.⁴ The study, published in 2011, noted that targeting these risk factors on a primary care level, and focusing on healthy lifestyles, could substantially improve the global stroke burden.⁶

Other targets for low-cost, high-efficacy interventions could include educational campaign programs, such as the Go Red for Women Campaign and World Heart Day, which have been effective in spreading education and increasing disease awareness.⁶ In addition, cost-effective interventions such as the polypill, which incorporates three medications into a single pill, could help reduce costs and improve compliance with medications.^{6, 7}

It also may be beneficial to incorporate new and innovative, yet still cost-effective, techniques to address the global burden of stroke. Some innovative approaches to address primary stroke prevention, namely by using smartphone technologies, have been suggested and are being tested. Researchers from New Zealand have developed the Stroke Riskometer app, which assesses responses to a short questionnaire and determines the five- and 10-year risk for stroke using a validated algorithm similar to the Framingham risk score.⁸ It also incorporates education, comparison with similar individuals and an opportunity to share risk assessment results with others. An update of this app allows for participation in an international epidemiological research study (the Reducing the International Burden of Stroke Using Mobile Technology, or RIBURST study), which involves more than 160 countries.

Besides the interventions on a patient and community level, countries with high rates of stroke mortality must set priorities that are attainable and commensurate to resources. Better definition of stroke traits and determinants in low- and middle-income countries are needed to develop culturally-specific stroke prevention strategies. International agencies must work together to develop more novel strategies to attack the stroke epidemic. The UN General Assembly already has attempted to do this by setting a goal of reducing mortality from non-communicable diseases by 25 percent by the year 2025.³ Collaboration, vision and innovation are needed to reduce the global stroke burden and the stroke disparities that exist between countries.

References

1. Mukherjee D, Patil CG, “Epidemiology and the Global Burden of Stroke,” World Neurosurg, 76 (2011): S85-90.
2. Deresse B, Shaweno D, Epidemiology and In-hospital Outcome of Stroke in South Ethiopia, J Neurol Sci, 355 (2015):138-42.
3. Berkowitz AL, Stroke and the Noncommunicable Diseases: A Global Burden in Need of Global Advocacy, Neurology, 84 (2015):2183-4.
4. O’Donnell MJ, Xavier D, Liu L, et al, Risk Factors for Ischemic and Intracerebral Hemorrhagic Stroke in 22 Countries (the INTERSTROKE Study): A Case-control Study, Lancet, 376 (2010):112-23.
5. Kim AS, Johnston SC, Global Variation in the Relative Burden of Stroke and Ischemic Heart Disease, Circulation, 124 (2011):314-23.
6. Fuster V, Voute J, Hunn M, et al., Low Priority of Cardiovascular and Chronic Diseases on the Global Health Agenda: A Cause for Concern, Circulation, 116 (2007)1966-70.
7. Johnston SC, Mendis S, Mathers CD, Global Variation in Stroke Burden and Mortality: Estimates From Monitoring, Surveillance and Modeling, Lancet Neurol, 8 (2009):345-54.
8. Feigin VL, Krishnamurthi R, Bhattacharjee R, et al., New Strategy to Reduce the Global Burden of Stroke, Stroke, 46 (2015):1740-7.

By Vladimir Hachinski, MD

Vladimir Hachinski

As dementia rises in prevalence, new approaches must be adopted in the treatment of the condition and efforts to prevent it.

Dementia means the loss of brain capacity severe enough to result in the loss of self-sufficiency. The incidence of dementia, which is rising globally, is largely driven by the aging population. Although dementia increases with age, it is not inevitable with age. Dementia represents the end stage of several processes, for which some are treatable and preventable.

Brain blood vessels (vascular) and Alzheimer’s disease represent the two most common pathologies leading to dementia. The changes of Alzheimer’s disease are characterized by the deposition of amyloid protein plaques and of tau protein aggregation forming tangles in neurons. The changes that lead to Alzheimer’s disease begin about 20 years before any symptoms appear. Many elderly individuals die with plaques and tangles without having had any trouble in life as a result. Similarly, most vascular disease is insidious. For each stroke that affects the body, five affect the mind, usually with the person being unaware of them.

While Alzheimer’s and cerebrovascular pathology occur commonly with age, mostly without symptoms, the combination doubles the chances that the dormant pathologies will result in dementia. Although cerebrovascular disease is treatable and preventable, scant attention has been paid to this component, present in 80 percent of Alzheimer’s patients.

Instead, the declared intention is to find a cure or disease-modifying drug by 2025. The idea of giving one drug to an amalgam of pathologies broadly defined as Alzheimer’s disease may prove as disappointing as the litany of failed trials that took place in the late 1990s and early 2000s aimed at stopping the damage that follows a stroke with a single drug. Since dementia has multiple causes, one must try multiple therapies, including addressing the one component that can be treated and prevented: the vascular one.

Dementia is not a threshold but a continuum. The process begins decades before any symptoms appear, a phase termed the “brain-at-risk stage.” The earlier the risk factors are recognized and treated, the better the chance of success.

Knowledge accrues in pieces, but is understood in patterns. Specialization fosters fragmentation and fiefdoms. It turns out that all major brain diseases result from different combinations of half a dozen mechanisms. By integrating this knowledge, researchers may discover that drugs developed for one purpose in one field may have application in another. If we only knew what we already know.

The Need for Multiple Therapies

The diagnosis of Alzheimer’s disease is notoriously imprecise, mainly because most patients harbor multiple pathologies. Even if a drug were 100 percent effective in blocking amyloid deposition, its effect might be obscured or overwhelmed by concomitant pathologies, for example brain vascular disease and its interactions, such as inflammation, if not treated at the same time. This calls for multiple therapies and new methodologies, such as platform trials to evaluate multiple therapies simultaneously. The lack of precision in diagnostic categories can be overcome by identifying specific contributing mechanisms leading to dementia and treating them. It is now possible to image vascular disease, amyloid and tau protein deposition and inflammation in the brain. Each of these mechanisms can be treated individually or in combination.

The evaluation of drugs can be accelerated by developing protocols in close reciprocal interactions with experimental work in a few advanced centers. These would continue with extensive protocols and thorough evaluation of patients. Once experience has been gained, a protocol could be simplified so that large numbers of patients could be enrolled. At predetermined intervals, statistically valid samples of patients following the simplified protocol would be studied by those following the extensive study protocol to make sure that they were similar.

In the era of big data and electronic records, it may be possible to do more sophisticated post-marketing surveillance and gain real-world knowledge of the effectiveness of different treatments.

Unhealthy diets, physical inactivity and tobacco and alcohol addiction represent identifiable risks for stroke and dementia and other non-communicable diseases targeted by the United Nations resolution of September 2011. In order to succeed, a three-step approach is required:

1. Information
2. Motivation
3. Enablement

Good information is essential, but by itself is no more effective than New Year’s resolutions. Motivation matters but is seldom addressed. Healthy lifestyles require a healthy environment, and policymakers have a particular role in creating it. They also have a leadership role in introducing legislation to curb tobacco and alcohol use and limit the consumption of unhealthy foods. They also have a major role in ensuring that our air is breathable. Air pollution can harm the lungs, damage the heart and afflict the brain. What happens in Beijing matters at Schloss Elmau: We share the same biosphere. Policymakers can follow the lead of Finland in considering health in all policies. Public health could be enhanced considerably through the leadership of non-governmental organizations. Additionally, policymakers can get help from international brain organizations, which can provide expertise and patient support groups, and can help to mobilize the public toward healthier lifestyles and risk-factor control, which may prevent or postpone major chronic diseases, including dementia.

Conclusions

Dementia results most often from a combination of Alzheimer’s and cerebrovascular pathologies and their interaction. Cerebrovascular disease is both treatable and preventable.

The diagnosis of dementia is imprecise, but it is now possible to identify and target the different mechanisms leading to brain deterioration. This will require multiple interventions and new clinical trial methodologies.

Dealing with the challenges of dementia will require not only new resources, but new thinking and different approaches as well.