Multiple sclerosis is a disease that raises a lot of interesting questions for people interested in biogerontology, human enhancement, and even cryonics. It raises questions about immunosenescence and draws attention to possible immune improvements for biological human enhancement. Biotechnologies to induce myelin repair may even be useful for the repair of cryopreserved brains. Before I discuss multiple sclerosis from these perspectives, let us take a closer look at this medical condition.

Multiple sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous system that results in axonal degeneration in the brain and spinal cord. In simple terms, multiple sclerosis is a disease wherein the body’s immune system attacks and damages the myelin sheath, the fatty tissue that surrounds axons in the central nervous system. The myelin sheath is important because it facilitates the conduction of electrical signals along neural pathways. Like electrical wires, neuronal axons require insulation to ensure that they are able to transmit a signal accurately and at high speeds. It is these millions of nerves that carry messages from the brain to other parts of the body and vice versa.

More specifically, MS involves the loss of oligodendrocytes, the cells responsible for creating and maintaining the myelin sheath. This results in a thinning or complete loss of myelin (i.e., demyelination) and, as the disease advances, the breakdown of the axons of neurons. A repair process, called remyelination, takes place in early phases of the disease, but the oligodendrocytes are unable to completely rebuild the cell’s myelin sheath. Repeated attacks lead to successively less effective remyelinations, until a scar-like plaque is built up around the damaged axons.

The name multiple sclerosis refers to the scars (sclerae—better known as plaques or lesions) that form in the nervous system. These scars most commonly affect the white matter in the optic nerve, brain stem, basal ganglia, and spinal cord or white matter tracts close to the lateral ventricles of the brain. The peripheral nervous system is rarely involved. These lesions are the origin of the symptoms during an MS “attack.”

In addition to immune-mediated loss of myelin, which is thought to be carried out by T lymphocytes, B lymphocytes, and macrophages, another characteristic feature of MS is inflammation caused by a class of white blood cells called T cells, a kind of lymphocyte that plays an important role in the body’s defenses. In MS, T cells enter the brain via disruptions in the blood-brain barrier. The T cells recognize myelin as foreign and attack it, which is why these cells are also called “autoreactive lymphocytes.”

The attack of myelin starts inflammatory processes which trigger other immune cells and the release of soluble factors like cytokines and antibodies. Further breakdown of the blood–brain barrier in turn causes a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins. These inflammatory factors could lead to or enhance the loss of myelin, or they may cause the axon to break down completely.

Because multiple sclerosis is not selective for specific neurons, and can progress through the brain and spinal cord at random, each patient’s symptoms may vary considerably. When a patient experiences an “attack” of increased disease activity, the impairment of neuronal communication can manifest as a broad spectrum of symptoms affecting sensory processing, locomotion, and cognition.

Some of the most common symptoms include: numbness and/or tingling of the limbs, like pins and needles; extreme and constant fatigue; slurring or stuttering; dragging of feet; vision problems, especially blurred vision; loss of coordination; inability to walk without veering and bumping into things; weakness; tremors; pain, especially in the legs; dizziness; and insomnia. There are many other symptoms, as well, such as loss of bowel or bladder control, the inability to process thoughts (which leads to confusion), and passing out. Some MS patients lose their vision and many lose their ability to walk. The symptoms are not necessarily the same for all patients and, in fact, an individual MS patient does not always have the same symptoms from day to day or even from minute to minute.

One of the most prevalent symptoms of MS is extreme and chronic fatigue. Assessment of fatigue in MS is difficult because it may be multifactorial, caused by immunologic abnormalities as well as other conditions that contribute to fatigue such as depression and disordered sleep (Braley and Chervin, 2010). Pharmacologic treatments such as amantadine and modafinil have shown favorable results for subjective measures of fatigue. Both drugs are well tolerated and have a mild side-effect profile (Life Extension Foundation, 2013).

It is estimated that multiple sclerosis affects approximately 85 out of every 100,000 people (Apatoff, 2002). The number of known patients is about 400,000 in the United States and about 2.5 million worldwide (Braley & Chervin, 2010). In recent years, there has been an increase of identified multiple sclerosis patients with about 50 percent more women reporting the disease. Indeed, between two and three times as many women have MS than men. Most patients are diagnosed between the ages of 20 and 50 but MS can strike at any age (National Multiple Sclerosis Society, 2013).

Incidence of multiple sclerosis varies by geographic region and certain demographic groups (Apatoff, 2002; Midgard, 2001). There is evidence that worldwide distribution of MS may be linked to latitude (Midgard, 2001). In the U.S., for instance, there is a lower rate of MS in the South than in other regions (Apatoff, 2002). Data regarding race shows 54 percent of MS patients are white, 25 percent are black and 19 percent are classified as other (Apatoff, 2002).

There are four disease courses identified in MS:

Relapsing-Remitting: Patients have clearly defined acute attacks or flare-ups that are referred to as relapses. During the relapse, the patient experiences worsening of neurologic function—the body or mind will not function properly. The relapse is followed by either partial or total recovery, called remissions, when symptoms are alleviated. About 85 percent of MS patients fall into this category (National Multiple
Sclerosis Society, 2013).

Primary-Progressive: The disease slowly and consistently gets worse with no relapses or remissions. Progression of the disease occurs over time and the patient may experience temporary slight improvements of functioning. About 10 percent of MS patients fall into this category (National Multiple Sclerosis Society, 2013).

Secondary-Progressive: Patient appears to have relapsing-remitting MS, but after time the disease becomes steadily worse. There may or may not be plateaus, flareups, or remissions. About half the people originally diagnosed with relapsing remitting will move into this category within 10 years (National Multiple Sclerosis Society, 2013).

Progressive-Relapsing: Quick disease progression with few, if any, remissions. About 5 percent of MS patients fall into this category at diagnosis (National Multiple Sclerosis Society, 2003).

The cause(s) of multiple sclerosis remain unknown although research suggests that both genetic and environmental factors contribute to the development of the disease (National Multiple Sclerosis Society, 2013; Compston and Coles, 2002). The current prevailing theory is that MS is a complex multifactorial disease based on a genetic susceptibility but requiring an environmental trigger, and which causes tissue damage through inflammatory/ immune mechanisms. Widely varying environmental factors have been found to be associated with the disease, ranging from infectious agents to Vitamin D deficiency and smoking. The debate these days revolves primarily around whether immune pathogenesis is primary, or acts secondarily to some other trigger (Braley & Chervin, 2010).

Risk factors for multiple sclerosis include genetics and family history, though it is believed that up to 75% of MS must be attributable to non-genetic or environmental factors. Infection is one of the more widely suspected non-genetic risk factors. A commonly held theory is that viruses involved in the development of autoimmune diseases could mimic the proteins found on nerves, making those nerves a target for antibodies. The potential roles of several viruses have been investigated including herpes simplex virus (HSV), rubella, measles, mumps, and Epstein Barr virus (EBV). The strongest correlation between a virus and MS exists with EBV—virtually 100% of patients who have MS are seropositive for EBV (the rate in the general public is about 90%)— but potential causality remains strongly debated (Ludwin and Jacobson, 2011).

It is important to keep in mind that infectious agents such as viruses may, in fact, have nothing to do with causing MS. The association of a virus with MS is based on increased antibody response and may be epiphenomenal of a dysregulated global immune response. “Proving” causality will require consistent molecular findings as well as consistent results from well-controlled clinical trials of virus-specific antiviral therapies (as yet to be developed). In the end, any theory concerning causality in MS should also account for the strong association with other environmental factors such as Vitamin D deficiency and smoking. Indeed, a landmark study found that, compared to those with the highest levels of vitamin D, those with the lowest blood levels were 62% more likely to develop MS. Additionally, a literature review evaluating more than 3000 MS cases and 45,000 controls indicates that smoking increases the risk of developing MS by approximately 50% (Life Extension Foundation, 2013).

Recently, researchers have pinpointed a specific toxin they believe may be responsible for the onset of MS. Epsilon toxin—a byproduct of the bacterium Clostridium perfringens—is able to permeate the blood brain barrier and has been demonstrated to kill oligodendrocytes and meningeal cells. Loss of oligodendrocytes and meningeal inflammation are both part of the MS disease process, and may be triggered by exposure to epsilon toxin.

The fact that females are more susceptible to inflammatory autoimmune diseases, including multiple sclerosis, points to the potential role of hormones in the etiology of multiple sclerosis. Interestingly, the course of disease is affected by the fluctuation of steroid hormones during the female menstrual cycle and female MS patients generally experience clinical improvements during pregnancy (Life Extension Foundation, 2013). Additionally, pregnancy appears to be protective against the development of MS. A study in 2012 demonstrated that women who have been pregnant two or more times had a significantly reduced risk of developing MS, while women who have had five or more pregnancies had one-twentieth the risk of developing MS compared to women who were never pregnant. (The increase in MS prevalence over the last few decades could reflect the fact that women are having fewer children.) A growing body of evidence supports the therapeutic potential of hormones (both testosterone and estrogens) in animal models of multiple sclerosis, but more research is needed to understand the pathways and mechanisms underlying the beneficial effects of sex hormones on MS pathology (Gold and Voskuhl, 2009).

No single test gives a definitive diagnosis for MS, and variable symptoms and disease course make early diagnosis a challenge. Most diagnoses are presumptive and are based on the clinical symptoms seen in an acute attack. Supporting evidence of these presumptions is then sought, usually from a combination of magnetic resonance imaging (MRI) of the brain, testing the cerebrospinal fluid (CSF) for antibodies, measuring the
efficiency of nerve impulse conduction, and monitoring symptoms over time.

As there is still much work to be done in understanding the nature of multiple sclerosis, a cure has yet to be discovered. Conventional medical treatment typically focuses on strategies to treat acute attacks, to slow the progression of the disease, and to treat symptoms. Corticosteriods such as methylprednisolone are the first line of defense against acute MS attacks and are administered in high doses to suppress the immune system and decrease the production of proinflammatory factors. Plasma exchange is also used to physically remove antibodies and proinflammatory factors from the blood.

The use of beta interferons is a longstanding MS treatment strategy, originally envisioned as an antiviral compound. Beta interferons reduce inflammation and slow disease progression, but the mechanism of action is poorly understood. Other immunosuppressant drugs such as Mitoxantrone and Fingolimod also slow disease progression, but are not used as first-line treatments due to their severe side effects. More recently, researchers at Oregon Health & Science University have noted that an antioxidant called MitoQ has been shown to significantly reverse symptoms in a mouse model of MS (Mao, Manczak, Shirendeb, and Reddy (2013).

Besides pharmacological treatments, MS patients may benefit from therapies (such as physical and speech therapy) and from an optimized nutritional protocol. Supplementation with Vitamin D, Omega-3 and -6 fatty acids, Vitamin E, lipoic acid, Vitamin b12, and Coenzyme Q10 appear to be of particular potential benefit (Life Extension Foundation, 2013). Until a definitive cause for MS can be defined and a cure developed, such strategies, including hormone therapy, offer possible ways to improve quality of life over the course of disease progression.

Unlike Alzheimer’s disease, there does not appear to be a Mendelian variant of MS that will invariably produce the disease in people who have the gene. A somewhat puzzling variable is that MS predominantly tends to occur between the ages of 20 and 50. This appears to exclude approaching MS as a form of immunosenescence. After all, if MS would be a function of the aging immune system, we would see progressively more cases of MS as people get older (or in AIDS patients), ultimately involving many very old people. More likely, MS is a non age-related form of dysfunction of the immune system that is triggered by environmental factors (such as a viral infection). While many discussions about the role of viruses in debilitating diseases like Alzheimer’s and MS still suffer from an incomplete understanding of cause and effect, it seems reasonable to conclude that enhancement of the human immune system can greatly reduce disease and improve the quality of life, even in healthy humans.

One potential treatment for MS is to induce remyelination (or inhibit processes that interfere with efficient remyelination). Stem cells can be administered to produce oligodendrocyte precursor cells to produce the oligodendrocyte glial cells that are responsible for remyelination of axons. While the myelin sheaths of these remyelated axons are not as thick as the myelin sheaths that are formed during development, remyelination can improve conduction velocity and prevent the destruction of axons. While the dominant repair strategies envisioned for cryonics involve molecular nanotechnologies that can build any biochemical structures that physical law permits, it is encouraging to know that specific stem cell therapies will be available to repair and restore myelin function in cryonics patients as damage to myelin should be expected as a result of (prolonged) ischemia and cryoprotectant toxicity.

An interesting possibility is that remyelination therapies may also be used for human enhancement if these therapies can be tweaked to improve conduction velocity in humans or to induce certain desirable physiological responses by varying the composition and strength of the myelin sheath in various parts of the central nervous system.

References

Apatoff, Brian R. (2002). MS on the rise in the US. Neurology Alert 20(7), 55(2).

Braley, Tiffany J., Chervin, Ronald D. (2010). Fatigue in Multiple Sclerosis: Mechanisms, evaluation, and treatment. Sleep 33(8), 1061-1067.

Compston, Alastair, and Coles, Alasdair (2002). The Lancet 359(9313), 1221.

Gold, Stefan M., and Voskuhl, Rhonda R. (2009). Estrogen and testosterone therapies in multiple sclerosis. Progress in Brain Research 175: 239-251.

Life Extension Foundation (2013). Multiple Sclerosis, in: Disease Prevention and Treatment, 5th edition, 947-956.

Ludwin, SK, and Jacobson, S. (2011). Epstein- Barr Virus and MS: Causality or association? The International MS Journal 17.2: 39-43.

Mao, Peizhong, Manczak, Maria, Shirendeb, Ulziibat P., and Reddy, P. Hemachandra (2013). MitoQ, a mitochondira-targeted antioxidant, delays disease progression and alleviates pathogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Biochimica et Biophysica Acta Molecular Basis of Disease 1832(12): 2322- 2331.

Midgard, R. (2001). Epidemiology of multiple sclerosis: an overview. Journal of Neurology, Neurosurgery and Psychiatry 71(3), 422.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, February, 2014

Book Review: The SharpBrains Guide to Brain Fitness: How to Optimize Brain Health and Performance at Any Age by Alvero Fernandez

Of all the organs in the human body, a cryonicist should be most concerned about the health and integrity of his or her brain. Thousands of books have been written about physical health and fitness, but very few address the topic of how to keep the brain fit and healthy. Happily, interest in brain fitness, once relegated to academics and gerontologists, is now taking root across America and the world.

The importance of lifelong learning and mental stimulation as a component of healthy aging has long been recognized and touted as a way to stay mentally alert and to stave off dementia in old age. As with physical exercise, “use it or lose it” appears to apply to our brains too. And now that scientists are learning more about neuroplasticity and how brains change as a result of aging, they have begun to test the effects of various factors on brain health and cognitive ability across the lifespan.

Unfortunately, like much health-related research, the results reported by the media have often been convoluted, confusing, and even contradictory. Products developed by overzealous entrepreneurs make outlandish claims and frequently don’t deliver the purported results. Consumers and professionals alike are left wondering what works and what doesn’t when it comes to maintaining our brains in optimal working condition.

To aid all those navigating the murky waters of brain fitness, enter SharpBrains—a company dedicated to tracking news, research, technology, and trends in brain health and to disseminating information about the applications of brain science innovation. In so doing, they “maintain an annual state-of-the-market consumer report series, publish consumer guides to inform decision-making, produce an annual global and virtual professional conference,” and maintain SharpBrains.com, a leading educational blog and website with over 100,000 monthly readers.

Most recently, SharpBrains has published a book on brain fitness called The SharpBrains Guide to Brain Fitness: How to Optimize Brain Health and Performance at Any Age. A compilation and condensation of information accumulated over the lifespan of the company, The SharpBrains Guide to Brain Fitness emphasizes credible research and goes to great lengths to provide the most up-to-date research results in specific areas of brain fitness, followed by interviews with scientists doing work in those fields. The goal of the guide is to help the reader begin to “cultivate a new mindset and master a new toolkit that allow us appreciate and take full advantage of our brain’s incredible properties…[by] providing the information and understanding to make sound and personally relevant decisions about how to optimize your own brain health and performance.”

The Guide begins by emphasizing that the brain’s many neuronal networks serve distinct functions including various types of memory, language, emotional regulation, attention, and planning. Plasticity of the brain is defined as its lifelong capacity to change and reorganize itself in response to the stimulation of learning and experience—the foundation upon which “brain training” to improve cognitive performance at any age, and to maintain brain health into old age, is predicated.

The difficulty of making sense of the scientific findings on brain health and neuroplasticity is discussed at length, with the finger of blame pointed squarely at the media for reporting only fragments of the research and for often reporting those results which are not most meaningful. The authors stress that “it is critical to complement popular media sources with independent resources, and above all with one’s own informed judgment.”

The following chapters go on to review what is known today about how physical exercise, nutrition, mental challenge, social engagement, and stress management can positively affect brain health. Along the way they provide dozens of relevant research results (as well as the design of each study) to support their recommendations. Reporting on all of those experiments is beyond the scope of this review, so if you are interested in examining them (and you should be!) please obtain a copy of the Guide for yourself or from your local library.

Physical exercise is discussed first because of the very strong evidence that exercise—especially aerobic, or “cardio,” exercise slows atrophy of the brain associated with aging, actually increasing the brain’s volume of neurons (i.e., “gray matter”) and connections between neurons (i.e., “white matter”). While much of the initial research supporting the effects of exercise on the brain came from animal studies, the authors report that “several brain imaging studies have now shown that physical exercise is accompanied by increased brain volume in humans.”

Staying physically fit improves cognition across all age groups, with particularly large benefits for so-called “executive” functions such as planning, working memory, and inhibition. A 2010 meta-analysis by the NIH also concluded that physical exercise is a key factor in postponing cognitive decline and/or dementia, while other studies have found physical exercise to lower the risk of developing Parkinson’s disease, as well.

But don’t think that just any moving around will do the trick. When it comes to providing brain benefits, a clear distinction is drawn between physical activity and physical exercise. Only exercise will trigger the biochemical changes in the brain that spur neurogenesis and support neuroplasticity. It doesn’t need to be particularly strenuous, but to be most beneficial it should raise your heart rate and increase your breathing rate.

Of course, adequate nutrition is also imperative in obtaining and maintaining optimal brain health. The SharpBrains Guide to Brain Fitness primarily highlights the well-known benefits of the Mediterranean diet, which consists of a high intake of vegetables, fruit, cereals, and unsaturated fats, a low intake of dairy products, meat, and saturated fats, a moderate intake of fish, and regular but moderate alcohol consumption. But I think it is safe to say that the jury is still out on the best diet for the brain, as evidenced by the recent popularity of the Paleo diet among life extentionists. And, of course, ethnicity and genetics are important, too. The authors do stress the importance of omega-3 fatty acids and antioxidants obtained from dietary sources, stating firmly that “to date, no supplement has conclusively been shown to improve cognitive functioning, slow down cognitive decline, or postpone Alzheimer’s disease symptoms beyond placebo effect.” This includes herbal supplements such as Ginko biloba and St. John’s wort.

Beyond what we normally do to keep our bodies healthy, the Guide also discusses the relative effectiveness of different forms of “mental exercise.” Perhaps you’ve heard that doing crossword or Sudoku puzzles will keep you sharp and alert into old age, or that speaking multiple languages is associated with decreased risk of Alzheimer’s disease. The good news is that these things are true—to a degree. The part that is often left out is that it’s the challenge of these activities that is important. As with physical activity vs. physical exercise, mental exercise refers to the subset of mental activities that are effortful and challenging.

Puzzles and games may be challenging at first, but they (and other mental exercises) can quickly become routine and unchallenging. In order to reap the most benefit from mental exercise, the goal is to be exposed to novelty and increasing levels of challenge. Variety is important for stimulating all aspects of cognitive ability and performance, so excessive specialization is not the best strategy for maintaining long-term brain health. If you are an artist, try your hand at strategybased games. If you’re an economist, try an artistic activity. Get out of your comfort zone in order to stimulate skills that you rarely use otherwise.

The SharpBrains Guide states that “lifelong participation in cognitively engaging activities results in delayed cognitive decline in healthy individuals and in spending less time living with dementia in people diagnosed with Alzheimer’s disease.” This is hypothesized to be because doing so builds up one’s “cognitive reserve”—literally an extra reservoir of neurons and neuronal connections—which may be utilized so that a person continues to function normally even in the face of underlying Alzheimer’s or other brain pathology. This observation raises another important point on which neuroscientists and physiologists do not yet fully agree. Will we all eventually get dementia if we live long enough without credible brain rejuvenation biotechnologies? This is a topic I would like to return to in a future installment of Cooler Minds Prevail.

Social engagement also appears to provide brain benefits. The NIH meta-analysis mentioned earlier concluded that higher social engagement in mid- to late life is associated with higher cognitive functioning and reduced risk of cognitive decline. Brain imaging studies indicate an effect of social stimulation on the volume of the amygdala, a structure that plays a major role in our emotional responses and which is closely connected to the hippocampus, which is important for memory.

Yet again, not all activity is equal. When it comes to social stimulation, “you can expect to accrue more benefits within groups that have a purpose (such as a book club or a spiritual group) compared to casual social interactions (such as having a drink with a friend to relax after work).” To keep socially engaged across the lifespan, seek out interactions that naturally involve novelty, variety, and challenge such as volunteering and participating in social groups.

“The lifelong demands on any person have changed more rapidly in the last thousand years than our genes and brains have,” The SharpBrains Guide explains in the intro to the chapter on stress management. The result? It has become much more difficult to regulate stress and emotions. It is great that we have such amazing and complex brains, but humans are among the few animals that can get stressed from their own thoughts. And while there are some (potentially) beneficial effects of short bursts of stress, high and sustained levels of stress can have a number of negative consequences. Those of note include: increased levels of blood cortisol which can lead to sugar imbalances, high blood pressure, loss of muscle tissue and bone density, lower immunity, and cause damage to the brain; a reduction of certain neurotransmitters, such as serotonin and dopamine, which has been linked to depression; and a hampering of our ability to make changes to reduce the stress, resulting in General Adaption Syndrome (aka “burnout”).

Research-based lifestyle solutions to combat stress include exercise, relaxation, socialization, humor and laughter, and positive thinking. In particular, targeted, capacity-building techniques such as biofeedback and meditation are recommended to manage stress and build resilience. Mindfulness Based Stress Reduction (MBSR) programs have provided evidence that meditative techniques can help manage stress and research shows that MBSR can lead to decreases in the density of an area of the amygdala which is correlated with reduction in reported stress.

So it appears that multiple approaches are necessary to develop a highly fit brain capable of adapting to new situations and challenges throughout life. “Consequently,” The SharpBrains Guide to Brain Fitness states, “we expect cross-training the brain to soon become as mainstream as cross-training the body is today, going beyond unstructured mental activity in order to maximize specific brain functions.”

There is growing evidence that brain training can work, but in evaluating what “works” we are mostly looking at two things: how successful the training program is (i.e., does it actually improve the skill(s) being trained?) and the likelihood of transfer from training to daily life. Building on an analysis of documented examples of brain training techniques that “work” or “transfer,” SharpBrains suggests the following five conditions need to be met for brain training to be likely to translate into meaningful real world improvements (condensed excerpt):

1. Training must engage and exercise a core brain-based capacity or neural circuit identified to be relevant to real-life outcomes.
2. The training must target a performance bottleneck.
3. A minimum “dose” of 15 hours total per targeted brain function, performed over 8 weeks or less, is necessary for real improvement.
4. Training must be adaptive to performance, require effortful attention, and increase in difficulty.
5. Over the long-term, the key is continued practice for continued benefits.

Meditation, biofeedback, and/or cognitive therapy in concert with cognitive training to optimize targeted brain functions appear to be winning combinations in terms of successful techniques facilitating transfer from training to real life benefits. Top brain training software programs, based on SharpBrains’ analysis and a survey of their users, include Lumosity, Brain games, brainHQ, Cogmed, and emWave.

In the end, brain fitness needs are unique to each individual and brain fitness claims should be evaluated skeptically. SharpBrains recommends asking several questions when evaluating brain fitness claims, particularly whether there is clear and credible evidence of the program’s success documented in peer-reviewed scientific papers published in mainstream scientific journals that analyze the effects of the specific product.

Of course, your own individual experience with the product is ultimately the most important evaluation of all. If you are ready to take the plunge into the emerging brain fitness market, The SharpBrains Guide to Brain Fitness is a good place to start, and I’m sure they’d appreciate your feedback as this field continues to develop.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, August, 2013

Any terminal illness is a terrible thing; but to a cryonics member, a brain-destroying neurodegenerative disease is the worst contemporary medical “death sentence” one can receive. There are several flavors of neurodegenerative disorders, many of which primarily affect the patient’s movement, strength, coordination, or the peripheral nervous system. And there are numerous contributory mechanisms in the causation of neurodegeneration, including prion infection and toxin related disease. But the most common – and the most feared – neurodegenerative disease is one that affects not movement, but cognition.

Of course, I am speaking of Alzheimer disease (AD). Originally described in a 51- year old woman by the Bavarian psychiatrist Alois Alzheimer in 1906, neuropathologists have increasingly recognized that AD is also the most common basis for latelife cognitive failure. Culminating in neuronal dystrophy and death leading to the progressive loss of memory and other cognitive functions (i.e., dementia), and affecting individuals of both sexes and of all races and ethnic groups at a rate of occurrence in the U.S. ranging from approximately 1.3% (age 65-74) to 45% (age 85-93), it is easy to see why AD has generated so much intense scientific interest in recent years.

In the recently published work “The Biology of Alzheimer Disease” (2012), most of what is known about AD today is described in detail in the various chapters covering topics such as the neuropsychological profile and neuropathological alterations in AD, biomarkers of AD, the biochemistry and cell biology of the various proteins involved in AD, animal models of AD, the role of inflammation in AD, the genetics of AD, and treatment strategies. The editors’ selection of contributions has resulted in the most up-to-date compendium on Alzheimer disease to date.

The book culminates in a chapter called Alzheimer Disease in 2020, where the editors extol “the remarkable advances in unraveling the biological underpinnings of Alzheimer disease…during the last 25 years,” and yet also recognize that “we have made only the smallest of dents in the development of truly disease-modifying treatments.” So what can we reasonably expect over the course of the next 7 years or so? Will we bang our heads against the wall of discovery, or will there be enormous breakthroughs in identification and treatment of AD?

Though a definitive diagnosis of AD is only possible upon postmortem histopathological examination of the brain, a thorough review of the book leads me to believe that the greatest progress currently being made is in developing assays to diagnose AD at earlier stages. It is now known that neuropathological changes associated with AD may begin decades before symptoms manifest. This, coupled with the uncertainty inherent in a clinical diagnosis of AD, has driven a search for diagnostic markers. Two particular approaches have shown the most promise: brain imaging and the identification of fluid biomarkers of AD.

Historically, imaging was used only to exclude potentially surgically treatable causes of cognitive decline. Over the last few decades, imaging has moved from this minor role to a central position of diagnostic value with ever-increasing specificity. The ability to differentiate AD from alternative or contributory pathologies is of significant value now, but the need for an earlier and more certain diagnosis will only increase as disease-modifying therapies are identified. This will be particularly true if these therapies work best (or only) when initiated at the preclinical stage. Improvements in imaging have also greatly increased our understanding of the biology and progression of AD temporally and spatially. Importantly, the clinical correlations of these changes and their relationships to other biomarkers and to prognosis can be studied.

The primary modalities that have contributed to progress in AD imaging are structural magnetic resonance imaging (MRI), functional MRI, fluorodeoxyglucose (FDG) positron emission tomography (PET), and amyloid PET. Structural MRI, which is used to image the structure of the brain, has obvious utility in visualizing the progressive cerebral atrophy characteristic of AD. Such images can be used as a marker of disease progression and as a means of measuring effective treatments (which would slow the rate of atrophy). Functional MRI, on the other hand, measures changes in blood oxygen leveldependent (BOLD) MR signal. This signal, which can be acquired during cognitive tasks, may provide the clinician with a tool to compare brain activity across conditions in order to assess and detect early brain dysfunction related to AD and to monitor therapeutic response over relatively short time periods.

FDG PET primarily indicates brain metabolism and synaptic activity by measuring glucose analog fluorodeoxyglucose (which can be detected by PET after labeling it with Fluorine-18). A large body of FDG-PET work has identified an endophenotype of AD – that is, a signature set of regions that are typically hypometabolic in AD patients. FDG hypometabolism parallels cognitive function along the trajectory of normal, preclinical, prodromal, and established AD. Over the course of three decades of investigation, FDG PET has emerged as a robust marker of brain dysfunction in AD. Imaging of β-amyloid (Aβ) – the peptide that makes up the plaques found in the brains of AD patients – is accomplished via amyloid PET to determine brain Aβ content. Historically, this has only been possible upon postmortem examination, so the utility of amyloid imaging is in moving this assessment from the pathology laboratory to the clinic. Because amyloid deposition begins early on, however, amyloid PET is not useful as a marker of disease progression.

The well-known hallmarks of AD, the plaques and neurofibrillary tangles first described by Alouis Alzheimer in 1906, were discovered in 1985 to be composed primarily of β-amyloid and hyperphosphorylated tau protein, respectively. Advances in our knowledge of Aβ generation and tau protein homeostasis have led to substantial research into disease-modifying drugs aimed at decreasing overall plaque and tangle load in an effort to halt neurodegeneration. Such treatments will likely be most effective if started early in the disease process, making sensitive and accurate fluid biomarkers of Aβ and tau especially important.

Outside of imaging, progress in AD diagnostics stems primarily from the assessment of fluid biomarkers of AD. These biomarkers are generally procured from the cerebrospinal fluid (CSF) and blood plasma and include total tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of of β-amyloid (Aβ42). These core biomarkers reflect AD pathology and have high diagnostic accuracy, which is especially useful in diagnosing AD in prodromal and mild cognitive impairment cases.

Because the CSF is in direct contact with the extracellular space of the brain, biochemical changes in the brain can be detected in the CSF. Assays to detect Aβ42 led to the discovery that Aβ42 in AD is decreased to approximately 50% of control levels, making the measurement of Aβ42 a useful clinical tool. Measurements of T-tau (around 300% of control in AD patients) and P-tau biomarkers (a marked increase in AD patients) in combination with Aβ42, however, provide an even more powerful diagnostic assay.

Fluid biomarkers for AD other than Aβ and tau have been posited, but positive results have been difficult to replicate. Novel biomarkers with the most promise inlcude the amyloid precursor proteins sAPPβ and sAPPα, β-site APP cleaving enzyme-1 (BACE1), Aβ oligomers, and other Aβ isoforms. Additionally, neuronal and synaptic proteins as well as various inflammatory molecules and markers of oxidative stress may prove valuable as CSF biomarkers. Studies of plasma biomarkers such as those investigating plasma Aβ have yielded contradictory results, but promising novel blood biomarkers for AD may be found in certain signaling and inflammatory proteins.

Taken together, progress in brain imaging and identification of fluid biomarkers hold great promise in improved diagnosis of AD cases. When combined with expected drug therapies we may be able to delay the onset of neurodegeneration and associated cognitive impairment significantly. In the meantime, early diagnosis is helpful in stratifying AD cases, monitoring potential treatments for safety, and monitoring the biochemical effect of drugs. For cryonicists, early diagnosis can help guide treatment and end-of-life care decisions in order to optimize cryopreservation of the brain.

So – back to the original question. What can we predict about the AD landscape in 2020?

Besides continued progress in early diagnosis through brain imaging and fluid biomarkers, the authors anticipate that advances in whole-genome and exome sequencing will lead to a better understanding of all of the genes that contribute to overall genetic risk of AD. Additionally, improved ability to sense and detect the proteins that aggregate in AD and to distinguish these different assembly forms and to correlate the various conformations with cellular, synaptic, and brain network dysfunction should be forthcoming in the next few years. Lastly, we will continue to improve our understanding of the cell biology of neurodegeneration as well as cell-cell interactions and inflammation, providing new insights into what is important and what is not in AD pathogenesis and how it differs across individuals, which will lead, in turn, to improved clinical trials and treatment strategies.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, April, 2013