The Aging Brain

Arnold Tweed 

“What’s your name?” This question is the basic unit of social interaction, one of the first questions you learn in studying a new language. Asked of a new acquaintance this indicates interest and a desire to be better acquainted. Asked of a child it suggests that you respect the child as a person, as an equal. But when asked of someone you have known for fifty years, someone you have worked with, harvested with, played cards with and chatted with almost every day of your life – it has an entirely different significance. It is a sign of advanced dementia, and the enquirer recognizes that something is missing. To even ask the question suggests that there is a struggle for recognition, that the other face is familiar – someone he knew – but that crucial item of identity, the name, eludes him.

This is the most tragic stage of Alzheimer’s disease, when the sufferer is losing contact with the essential parts of his past, and realizes it is happening. He tries to preserve his shrinking world by filling in the missing pieces, but immediately loses them. This was Roy in 1972, on his last visit to his old community, where he had been born, gone to school, and farmed for fifty years. Where he had known everyone in the community since they had played together as children. But now he couldn’t recall the name of an old neighbour and close friend.

We had had a long talk on the drive out. For some time Roy had tried to deny his memory loss but now he was facing reality. He knew his memory was failing and he was afraid. How could he carry on every day activities, cope with finances, enjoy his family, if his memory were gone? How do you manage when your past is lost?

Roy was my father-in-law. He was small, wiry and quick – quick both of movement and wit. He did chin-ups with one arm, not just one but thirty in a minute. A farmer who had survived the dirty thirties, he was by necessity an inventor. When he needed a new implement he made it – one wet year, when the rains delayed harvest, he made a swath turner- so the swath would be exposed, dry quicker and be ready to combine sooner. He had a name for every animal on the farm and called each by name. When an issue of conduct rose he invented a cautionary metaphor. Gluttony, especially when new vegetables were so enticing in the spring, was discouraged by citing the tragic case of “the girl north of Crandall,” who ate so much she burst. And Roy was a good neighbour – when a neighbour needed help Roy was there.

On this final visit to his old community he knew that these parts of his life were slipping away. Within a shell of hesitancy and uncertainty was a person struggling to recognize the shadows of his fading world. Fortunately, he didn’t realize that even those shadows would soon disappear.

Alzheimer’s is the most tragic disease that afflicts mankind. It robs one of his past, of the memories that sustain us in old age. Without memory and recollections there can be no sense of identity, no concept of self. Without a past there is no future. The victim of Alzheimer’s is eventually restricted to the immediate present – the sensations of the moment and their gratification. Hunger is sated by eating, thirst by drinking, itch by scratching. Even the sensory present becomes narrower and narrower. Eventually eating and defecation become the only activities that give satisfaction, and, since all other sensory input has no meaning, sleep consumes the remainder of the day.

Is Alzheimer’s the inevitable price to be paid for a long life? Not necessarily, but certainly the risk increases after age 65 and about 25-35% of those who live beyond 80 will eventually be affected (See Figure I below). It is the most common of the “dementias”, a group of age related degenerative brain diseases (Alzheimer’s, Parkinson’s disease, Huntington’s, vascular dementia). They impair cognitive function by specific pathological processes, and, are different from the biological changes of aging, the changes that we call senescence. Senescence is a normal aging process whereas dementias have pathological causes. There may appear to be little difference between the senile and the demented, but the distinction is important.

Senescence affects all organs of the body, the brain included. But we all age differently and cognitive decline varies greatly from one person to another. Some of us will reach extreme age with virtually no sign of cognitive deterioration. A partial explanation for this variability and a cause for optimism is that the brain at all ages retains a remarkable adaptive ability called plasticity; some functions can shift from an overworked part to a healthier area and even from one side to the other. A younger brain shows more specificity (localization) of function while in an older brain it is more diffuse (de-differentiation). As a result, the functional map of an aged brain may bear little resemblance to that of a young brain.

Senescence is selective in another way, some cognitive functions are more susceptible than others.  Memory is the first casualty but memory loss is also selective; working memory and episodic memory are the first affected.

Working memory is the ability to retain a set of information (in short term memory) and use it to plan, organize and execute tasks. When working memory slows down, complicated tasks such as complex problem solving take longer and are less efficient. This may be hard to detect unless one deliberately challenges the higher cognitive functions, for example by playing chess or bridge. Often, our major frustration will be in keeping a set of new information intact. This is evident in everyday experiences – for example going to the garden shed, stopping on the way to rearrange the furniture on the deck, and arriving at the shed forgetting why I went.

Episodic memory is the recall of life experiences, the personal events of your life, linked to specific times and places. It is the important bits and pieces of your life stretching back to childhood. Senescence impairs the processes of forming (encoding), storing and retrieving episodic memories. Old, ingrained memories are better preserved though retrieving them may take longer. You may remember your first day at school but what did you have for breakfast this morning? Did anyone visit you yesterday? Who? Where did you put your keys? Of practical importance, episodic memory is the fundamental skill for independent living.

The good news is that we usually compensate well for the minor deficiencies, which mainly affect “fluid intelligence”. The concepts of “fluid intelligence” and “crystallized intelligence” were introduced by Dr. Raymond Cattell who was at the University of Illinois in the 1940s. Fluid intelligence is the ability to process new and novel information, to find creative solutions to problems, to “think on your feet.” Although these slow down, other types of memory, factual (semantic) and procedural memories are well preserved. Those are what Cattell called crystallized intelligence, our generalized, encyclopedic memory bank. We remain proficient at tasks that use this type of memory: cross-word puzzles and, hopefully, penning stories.

One special form of crystallized intelligence that is particularly well preserved is called procedural memory: walking, riding a bicycle, playing a musical instrument, reciting poetry.  One very famous case is a British musician, Clive Wearing (1938 – ), an accomplished chorus master who has complete amnesia due to a viral meningitis that destroyed critical parts of his brain (the hippocampus). His memory span is only a few seconds, his previous life is a blank slate. He lives in the 10 seconds of the present but recognizes his wife (though not her name), speaks fluently with an adequate vocabulary, and when given a baton and an orchestra can conduct flawlessly. His episodic memory is totally gone but his procedural memory is well preserved.

There is more good news. We might expect that older people would be less happy; they have plenty of reason to be. And, in fact, clinical depression is more common in the elderly, though more difficult to recognize and seldom treated. However, the “paradox” of aging is that on average older people are more satisfied, better adjusted, more stable emotionally and have better social relationships. Life gets better as we age; in fact life satisfaction scales peak at about age 65. The reasons for this are uncertain but it may be simply a matter of choice, older people have a shorter time horizon, they don’t have time to waste on negative thoughts.

The critical question is – can we slow the aging process? The Stanford Center on Longevity and the Max Planck Institute for Human Development in Berlin convened a conference of world experts in 2014 to examine the evidence. Their advice was to be wary of easy solutions – brain games – that are being promoted commercially. The main conclusion of the world’s best minds in this field was remarkably prosaic, “try to lead a physically active, intellectually challenged and socially engaged life.” How does that translate into everyday life? In most studies physically active means a half hour of walking a day. If you can’t walk ride a bicycle; if you can’t do either swim; if you can’t swim do aqua-aerobics. That is the easy part but how do we keep intellectually challenged after we retire? The key concept appears to be “productive – engagement”. These are activities in which you are intensely mentally involved: taking a university course, learning a new language, or a hobby such as wood-working. Dr. Denise Park in at the University of Texas at Dallas is a pioneer in these studies and has found that these activities improve the specific functions that deteriorate with aging – executive memory and episodic memory. The control group, assigned to “receptive (passive) – engagement” showed the effects of normal aging. Several well conducted experiments have now confirmed that the improvements are statistically significant.

The evidence is there – physical, mental and social stimulation may slow the aging process. Old folks benefit from doing the same things young people do, perhaps even something as banal as video games. They probably benefit least from watching TV and listening to retired entertainers. There is mounting support for a holistic approach to aging which emphasizes physical fitness, healthy eating, social stimulation, and cognitive exercises. Many of us can expect to stay physically active, mentally productive and socially involved into our eighth decade. Old age may actually become a time for new adventures and new experiences.

The outlook for those with Alzheimer’s and other degenerative brain diseases is less optimistic. Though the early cognitive dysfunctions are often similar to normal senescence, nothing is spared. Getting lost is often a critical sign. Roy went for a walk one day, just a block or two, and was found hours later a mile away and totally disoriented. This happened again, and again, and finally required his admission to a chronic care facility. He adapted well to his new environment; the locked ward seemed to give him a sense of security. His old home quickly became unfamiliar territory and he was always anxious to get back to the security of the care home. Within a few months he was totally dependent on their care.

The onset of Alzheimer’s dementia is often slow, but there are no definitive tests, the early diagnosis is usually tentative and the window of opportunity for planning and preparation may be short. Roy was in that window on his last visit to his home town; he understood that he was losing his grip on his world. That is the time for family, emotional and spiritual reconciliation – for divesting oneself of life’s burdens. There may even be a time in the future when end-of-life issues can be a personal choice, so that those at risk can plan for their terminal care and leave directives that will be honoured. Treatment in the later stages is solely supportive and our best hope lies in medical research (see Technical Notes).

There is another philosophical viewpoint we might consider. One of the most influential books of the 20thC was the Pulitzer Prize winner of 1974, The Denial of Death, written by Ernest Becker. His message is simple – “It is our mortality, specifically the knowledge that we are mortal, that gives meaning to our lives. Without that certainty our lives, like those of the immortal Greek Gods, would be trivial and pointless.” It may be a comfort, for some, to read Becker’s book.

How did Roy fare in the home? He went through all the stages of dementia – dependency and the progressive shrinking of his world – and eventually succumbed to pneumonia, ten years later. Our most famous Canadian physician, Sir William Osler, called pneumonia “the old man’s friend.” He was right; it is a gentle release from a life that has lost all meaning.

 

Suggested Reading (Cabeza, Nyberg et al. 2017):

The Aging Brain, 2013, by Thad A. Polk, Professor of Psychology, University of Michigan. Published by The Great Courses, 4840 Westfields Blvd., Chantilly, Virginia as a series of 24 lectures.

Cabeza, R., L. Nyberg and D. C. Park (2017). Cognitive neuroscience of aging : linking cognitive and cerebral aging. New York, NY, United States of America, Oxford University Press.

 

 

Figure I showing that the prevalence of dementia in the aging population approximately doubles every five years after age 65. From Google search: “Images for dementia statistics by age.” About 30-35% of the total population over age 85 will be expected to suffer some form of dementia – more than half will be due to AD and women will outnumber men 2:1.

 

Figure II showing that past age 80 women with dementia outnumber men, perhaps only because women live longer. From Google search: “Images for dementia statistics by age.”

 

Technical Notes:

The Cognitive Neuroscience of Aging (CNA) is a relatively new discipline, mainly research oriented, that combines elements of Cognitive Psychology and Clinical Neurology. A summary of current research and concepts can be found in a recent review (2017), Cognitive Neuroscience of Aging, edited by Roberto Cabeza, Lars Nyberg and Denise C. Park. Other sources are noted in the Suggested Reading list above.

Cognitive psychologists have developed a number of tests which can identify cognitive decline with aging and disease. Clinical neurology has provided the clinical tools and investigative techniques to assess the associated clinical deficits, changes in brain structure and corresponding changes in regional brain function. The most useful techniques have been the MRI and functional MRI (fMRI). Combined, they provide a comprehensive picture of the aging brain.

Two regions of the brain, the Hippocampus (HPC) and Pre-Frontal Cortex (PFC), play critical roles in the cognitive declines of both normal senescence and Alzheimer’s dementia (AD). Selective atrophy in these regions, and in certain white matter tracts, is an early feature of both conditions and the cognitive functions first impaired are also located in these regions.

The PFC is the frontal part of the human cerebral cortex. This is the newest part of the brain in evolutionary development and serves important higher cognitive functions including working memory and executive functions. Decline in these higher functions is probably multifactorial, due to both neuronal loss and impairment of processing speed. Slowing down in communications, a decline in processing speed, is common with aging and is probably also fundamental to other declines in performance.

Because episodic memory is our most important asset for independent living – and cognitive deficiencies in episodic memory are socially disabling – this discussion will emphasize the cognitive neuro-physiology of episodic memory. This is also a major interest of researchers in the CNA.

When psychologists discuss episodic memory, they define an episode as a conscious personal experience (an item) occurring at a specific time and place. In order to be a conscious experience an episode must activate areas of the cerebral cortex that serve sensory input, association and self-awareness. The resultant activation patterns can be registered on fMRI or PET scans and mapping such episodes is one of the fundamental preoccupations of Cognitive Neuroscience.  We may have hundreds of these episodes every day and, because they have no qualities that warrant remembering, most rapidly fade away. An episode does not become a memory unless hippocampal (HPC) structures are activated. Surgical ablations, done more than 50 years ago, showed conclusively that the HPC is essential for storage and retrieval of episodic memory. Current research, mainly in animal labs, is concentrating on how the HPC is organized to perform these tasks.

The first step in memory formation is the allocation process by which a memory item is allocated to a discrete set of neurons in the HPC. However, a single item of memory is of limited value and achieves more significance when viewed within the context of related items, a function that has been called associative memory. Think of the difference between a still photo and a video. Based on these assumptions scientists have focused their HPC research on the processes of allocation and the linkages that support associations between related items of memory.

Part of the answer may lie in a gene called CREB, which is essential for long term memory formation. The CREB proteins are transcription factors that regulate expression of other genes that are involved in forming and maintaining synapses between neurons. They are the molecular architects of synaptic connections linking networks of neurons.

The HPC (also called Ammon’s horn) acquired its strange name because of its resemblance to a sea-horse or goat’s horn. It is located in the medial temporal lobe, part of the telencephalon, and part of a complex group of interrelated structures in the medial temporal gyrus. The hippocampal complex, that is the hippocampus and related nuclei, is found in all mammals and serves several critical functions. One of the most basic is spatial mapping of physical surroundings. Watch a dog in a new garden running about the periphery, sniffing and exploring. He is forming a cognitive map in his hippocampus of his new domain, based on visual and olfactory representations. Our hippocampi retain the same functions and when we lose our spatial maps we lose our orientation and get lost, an early feature of AD.

Episodic memory is higher in the phylogenetic scale but probably utilizes variations of the same circuitry as spatial mapping. Current computational models hypothesize that these networks support two processes, pattern separation and pattern completion.  Pattern separation is the process whereby new associative information is quickly distinguished as distinct and separate from previously stored material, and is allocated to a discrete set of neurons with strong synaptic connections. Impairment of this function would impair memory formation and make it more vulnerable to distractions. Pattern completion is a process in which incomplete or degraded representations (clues) are completed by reference to stored memories. This facilitates retrieval since all memory clues are likely to be partial or degraded and impairment of this function would lead to slower and incomplete retrieval.

Parallel research with both animal and human subjects is beginning to provide evidence which supports these models and suggests a physiological framework for understanding episodic memory and its degradation in senescence and AD.

The allocate-to-link hypothesis is currently being investigated by Alcino J. Silva at the University of California, in L.A. Briefly, the hypothesis states that allocation, at least in the HPC, is not random – a memory will be selectively imprinted on neurons that are in a higher state of activation, that have expressed more CREB protein – and that set of neurons will remain in a higher state of activation for several hours. New and related episodes experienced within that time frame will be imprinted on a set of neurons that overlaps the previous set and these memories become linked. Recall of one memory, or a part of one, will recall the other. Research in several labs has confirmed these findings. Stimulation of neurons in one set provokes recall of the episode stored in the overlapping set.

A general theory of episodic memory might look like this. A poignant episodic memory (the stimulus) activates a receptive set of neurons in the hippocampus. That set is defined by its synaptic connections, which must be strengthened and maintained to retain the memory. The formation and maintenance of these synaptic connections is a least partly under genetic control, the CREB gene. We also know that that older animals (mice) have lower levels of CREB protein than do younger animals. Both pattern separation and pattern completion can be explained by synaptic connections and linkages. Weaker synaptic connections would reduce the cohesion within a set of neurons and impair pattern separation, and thus the ability to protect that set of neurons from distractions. At the same time it would also impair pattern completion by making it less likely that stimulation of neurons in one set would activate another or overlapping set.

This research is still at an early stage. Although there is no surety that manipulating the CREB gene or the proteins it encodes will have any significant effects on human cognition, this is certainly a potential goal for further investigation, particularly in the aged.

 

Author: Arnold Tweed

Retired anesthesiologist living in Toronto, Canada.