From 2002 through 2004, Henry was still healthy enough mentally and physically to take part in formal cognitive testing. Because of his motor difficulties, it became uncomfortable for him to travel to MIT, so we drove to Bickford to carry out our behavioral experiments. During this time, however, Henry did make several trips to the Mass General Martinos Center for Biomedical Imaging for a series of MRI scans. He traveled by ambulance to ensure that he would have a comfortable ride. Each time he came for one day, and we hired two aides to care for him. As a result of cutting-edge advances in MRI, these studies gave us a clearer picture of Henry’s lesions and new insights about his aging brain. Researchers used the MRI images to create a computerized model of his brain that could be compared with those of healthy male participants of the same age. The scientific question was whether the changes in Henry’s brain were equivalent to or exceeded those in the controls. A related question that emerged as Henry aged was whether his brain would show evidence of aging-related disease, independent of the damage caused by his 1953 operation. Having this information would give us a complete picture of his neural infrastructure and help us understand his cognitive capacities late in life.2
Even to the naked eye, a normal eighty-year-old brain looks dramatically different from a normal twenty-year-old brain. The total volume is reduced in the older brain, and consequently the fluid-filled spaces in the middle of the brain—the ventricles—become larger. Because of this tissue shrinkage, the valleys—sulci—are deeper, and the peaks—gyri—are thinner, thus accentuating the folds in the cortex, the outer surface of the brain. The loss of mass is not uniform, however; some areas look markedly smaller in old age, while others remain relatively unchanged. With modern MRI technology, we can spot these changes in healthy participants over as short a time as one year. The brain atrophy observed in healthy older adults told us what to expect in Henry’s brain, simply as a consequence of natural aging processes. Research in my lab also alerted us to the importance of white matter integrity for the performance of complex tasks.3
Some scientific questions linger: how do these physical changes in the brain correspond to changes in specific cognitive abilities, and which of the identified late-life alterations best explain cognitive loss? Even when people age successfully, they show some cognitive decline. Hardest hit are working memory—for example, mentally dividing a large dinner bill by fourteen to determine the amount that each guest owes—and long-term memory—remembering the names and identities of all the people encountered at a wedding. All complex processes in the brain, such as memory and cognitive control, depend on interactions within and among specific brain regions. Because white-matter tracts, the lines of communication, must be kept open and running smoothly for optimal function, it is reasonable to expect that damage to white matter in a particular region would impair the cognitive capacities that depended on that region.4
Because I kept in touch with Henry and had access to his nursing home records, I was aware of the ups and downs during this last third of his life. By 2000, his gradual decline had continued. He now had some difficulty or perhaps unwillingness to feed himself, even though he continued to gain weight. He had few seizures but showed some cognitive impairment—for example, decreased concentration, lessened ability to process instructions, and increased confusion. An additional loss of coordination and strength made it challenging for Henry to travel around the nursing home, and he continued to experience falls. His social life also went downhill; he often chose not to participate in group activities and had trouble making friends, instead showing frequent periods of irritability, anger, and obsessive behaviors, such as a preoccupation with going to the bathroom. He had a tendency to worry and become impatient; as he observed, “I’m always on edge.” His speech was slurred, perhaps from too much medication, and he slept a lot in his geriatric chair. From time to time, Henry’s oxygen level was low, so the staff gave him oxygen via tubes in his nostrils. Usually, he took the tubes out, and once put them in his urinal.
In 2005, Henry had several grand mal seizures, his cognitive and motor capacities declined further, and he became completely dependent on others. In spite of these handicaps, his daily life seemed to have improved; he attended activities three to five times a week, and according to his chart was “very social with his peers.” He still enjoyed Bingo, crossword puzzles, and word games, and one note described him as a “pleasant interesting person—a joy to talk with.” It is safe to say, however, that by this time Henry was demented, based on the global deterioration of his cognitive capacities.
What is the difference between amnesia and dementia? Pure amnesia, such as Henry experienced after his operation, consists of memory impairment without additional cognitive deficits. In contrast, dementia is characterized by severe memory loss compounded by defects in multiple cognitive domains—language, problem solving, math, and spatial abilities. Dementia goes far beyond the changes that accompany healthy aging, and by 2005, Henry had crossed over from amnesia plus healthy aging to amnesia plus dementia. We found its neural underpinnings in his MRI scans.
The imaging studies we conducted from 2002 to 2004 gave us a more complete picture of Henry’s aging brain and complemented our years of rich clinical observations. The effects of his operation were compounded both by changes related to his advancing age and by new brain abnormalties. The MRI scans showed small strokes in his gray and white matter that were not connected to his operation, but that stemmed from aging-related disease—probably advanced white-matter disease caused by hypertension. These localized regions of dead brain tissue caused by a lack of blood and oxygen were in the expected areas for brain disease from high blood pressure. We also saw small strokes in gray-matter structures under the cortex, such as the thalamus, an area that integrates sensory and motor activities, and the putamen, a motor area under the frontal lobes. An accumulation of such strokes was the likely cause of Henry’s dementia. A further correlate of his dementia came to light when we compared the thickness of his cortex to that of control participants. We found that thinning had occurred to a greater extent than normally expected for his age and was widespread across his entire cortex, rather than focused in certain areas as we typically see with healthy aging.5
We had not seen most of these alterations in his 1992 and 1993 scans, suggesting that they had originated recently. We knew from our MRI studies in healthy older adults that their cognitive capacities are closely linked to the integrity of white-matter tracts in their brains: participants with the most intact white matter had the best memory-test scores. Knowing this, my lab focused on the status of Henry’s white-matter communication system. We found widespread damage to Henry’s white matter—more extensive and severe than normally expected from healthy aging. A further analysis based on diffusion-tensor imaging showed that the white-matter fibers had lost some of their structural, and presumably functional, integrity. He also had white-matter damage consequent to his operation.
We will pursue our examination of Henry’s white matter by analyzing the MRI images of his autopsied brain. A new tool, tractography, will allow us to trace specific fiber bundles to localize white-matter damage. We will compare the results of this analysis with the anatomy derived from studying the actual white-matter tracts in his autopsied brain. Based on the characteristics of the fiber-bundle damage, Matthew Frosch, Director of Neuropathology at Mass General, will be able to distinguish the specific white-matter pathways related to Henry’s operation from those related to the strokes. We will know definitively what kind of dementia Henry had after Frosch conducts a detailed neuropathological examination of his brain tissue. Many lingering questions about Henry’s brain must await upcoming microscopic analysis.6
During the 1980s, when I was studying Alzheimer disease, I learned the importance of brain donation: a definitive diagnosis of the disease can be made only at autopsy. As Henry began to decline, I focused on ensuring that we would be able to study his brain after he died. Although we could learn a great deal th
rough brain imaging, the only way to learn conclusively about the status of the remaining tissue was to examine it microscopically. We would then know with certainty what gray matter and white matter had been removed during his operation and what was spared. Additionally, we could document any abnormalities related to advanced age and aging-related diseases. I explained to Henry and his court-appointed conservator, Mr. M. (Mrs. Herrick’s son) the importance of examining Henry’s brain after his death, and asked whether Henry would donate his brain to Mass General and MIT. They completed an Authorization for Brain Autopsy form in 1992.
In 2002, I assembled a team of neuroscientists for the first of many meetings to plan the details of what we would do step by step when Henry died. I selected colleagues who brought different kinds of expertise to the project in hopes that we could do something extraordinary. Henry had already contributed much to the world’s knowledge of memory, and I wanted to extend the research by applying cutting-edge techniques for imaging, preserving, analyzing, and disseminating information about his brain. The team included neurologists, neuropathologists, radiologists, and systems neuroscientists from Mass General, the University of California, Los Angeles, and my lab at MIT. Our discussions, carried out over the next seven years, identified several key tasks and the order in which they had to be carried out.
We knew it would be vital to harvest Henry’s brain as soon as possible after he died, before the tissue deteriorated. To reach this objective, we laid out a set of plans in collaboration with Bickford—having a nurse or doctor officially pronounce Henry as dead and noting the time of death, packing his head in ice to preserve his brain, and arranging for a funeral home to transport his body to the Martinos Center at Mass General for pre-autopsy scanning. We created a telephone call-list to notify all the researchers that Henry’s body was on the way. Once there, it would be necessary to transfer it from the gurney it traveled on to a smaller nonmagnetic gurney and from there into the scanner, all the while adhering to the safety precautions required for dealing with human tissue and fluids. After this in situ scanning (imaging of the brain in the head), we would transport Henry’s body to the Mass General Morgue so Frosch could remove Henry’s brain from his skull. The neuropathology photographer would be on hand to catch the first photographs of Henry’s physical brain. His body would then be moved to another area in the pathology department where a general autopsy would be performed. To preserve the brain, the neuropathologist would have to order the proper solution in advance, so he would be equipped when the time came. After much debate, we decided that we would scan Henry’s brain again, after it had been preserved for ten weeks. We deliberated about using a three Tesla scanner or a seven Tesla scanner, and ultimately decided to use both. Pilot scans on other autopsied brains had established that the procedures were safe.
We also worked out the logistics of transporting a brain from Boston to San Diego, California, where it would eventually be frozen in gelatin and cut into ultra-thin sections for microscopic analysis. We would be right on the threshold of looking at the actual neurons inside the most famous brain in the world. The big payoff would come when experts in medial temporal lobe anatomy and neuropathology would stain and examine selected sections, yielding answers to questions about Henry’s brain that had been waiting in the wings for decades.
Our goal during Henry’s final years was to understand the abnormalities we documented in his brain in relation to his clinical condition. Could these anatomical changes account for his slipping mental status? I administered a few cognitive tests during my yearly visits, and each time invited along a colleague from the Mass General Neurology Department to update Henry’s neurological condition. These annual evaluations uncovered a clear pattern of cognitive decline due to aging-related abnormalities in his brain—documented in his MRI scans—in concert with toxic side-effects from multiple psychoactive medications. Dehydration may also have played a role in his compromised mental status. I do not know how much water Henry drank or the extent to which other factors, such as medication side-effects, contributed to his dehydration, but given his characteristic silence about hunger and thirst, he likely did not ask for water. Based on our clinical observations during Henry’s life, we could not specify with confidence the cause of his dementia. It could have been Alzheimer disease, vascular dementia, or a combination of abnormalities.
In June 2005, when Henry was seventy-nine, I drove down to see him with a neurologist who had often examined him at the MIT CRC and knew him well. At the time of our visit, Henry’s blood pressure was high, and he weighed 218 pounds. The examination revealed that although Henry’s speech was slightly slurred and difficult to understand, he named four out of five common objects (he missed stethoscope), performed five gestures on command (such as salute), and could mimic gestures. His muscle strength was reduced, especially in his legs—not a surprise considering that he had spent recent years in bed or in a wheelchair.
After the neurologist completed his exam, I stood next to Henry’s wheelchair and administered a few cognitive tests. Encouragingly, his digit span—his immediate memory span—had not changed; he could still repeat five digits back to me. So when I said, “Seven, five, eight, three, six,” he immediately responded, “Seven, five, eight, three, six.” His performance indicated that when he was at his best, Henry could still pay attention, follow directions, and respond appropriately.
Bolstered by that success, I asked him to define a list of vocabulary words. Some of his definitions were concrete, a general characteristic of brain-damaged individuals; when I asked him the meaning of “winter,” he said, “cold,” and for “breakfast” he said, “eating.” For other words, however, he gave excellent definitions, telling me that consume means “eat,” terminate means “end,” and commence means “start.”
I next evaluated his ability to name common objects by showing him line drawings and asking him to tell me what they were. This task, often used in tracking disease progression in Alzheimer patients, measured his semantic knowledge, the meaning of words. Of the forty-two pictures, he named more than half correctly, but this score was well below those of healthy control participants. In some cases, his response was marginal. When I showed him a tennis racket, he said, “for tennis,” and a toboggan, “bobsled.” He clearly knew what these pictures depicted but could not access their correct names. I am sure that fatigue played a role in his impoverished performance because at one point I noticed that he was nodding off. Nevertheless, Henry’s brain had clearly lost some semantic knowledge.
Henry’s lethargy was surely in part a result of the medications he was taking. His doctor had prescribed Xanax, Seroquel, and Trazodone. According to the physician’s order sheet, Henry received these medications for agitation, anxiety, obsession with his bowels and bladder, and depression. These psychiatric symptoms were not part of his amnesia but were instead connected to his progressive dementia and undiagnosed colon cancer. At this point in his life, Henry, sadly, was a pharmacy in a wheelchair.
By 2006, Henry was declining sharply. The neurologist found numerous changes in his condition since the previous year. His blood pressure was low, although it had been quite high the previous year. He was somnolent, performed only three out of five gestures, and had limited arm movement. His strength in his hands and legs had decreased further. We speculated that the decline in his condition was due to new small strokes, brain degeneration, heart disease that affected the blood supply to his brain, or sedating medications—or a combination of these factors. The neurologist recommended that Henry’s doctor at Bickford reevaluate the need for Xanax, Seroquel, and Trazodone. Henry required full-time care, spending his days in bed or in a geriatric chair, which reclined and was more comfortable and supportive than a standard wheelchair. He could feed himself now and again but most of the time needed help from the staff. He sometimes participated in group activities, especially Bingo and a daily coffee hour at which the residents did physical exercises. Henry could be attentive but tired easil
y.
By 2007, Henry’s lethargy and confusion had increased. During our three-hour examination, his level of alertness waxed and waned from fully alert and interactive to sleepy, with his eyes closing from time to time. He made good eye contact and had an excellent social smile. When he was wheeled into the examination room, he looked around with interest at his four visitors and smiled at everyone. When we asked him how he was, he said that his right knee hurt. Knowing the scarcity of his pain reports in the past, this new pain must have been extreme to cause him to complain. The physical exam showed that his knee was mildly swollen and warm, so the neurologist prescribed ibuprofen and recommended that Henry increase his intake of fluids to combat dehydration. We could see that he was dehydrated because when the physician gently pinched the skin on the back of his hand, it did not bounce back as it would in a well-hydrated person. He was still oversedated, so the physician also recommended decreasing the doses of several medications.
By this stage, Henry’s language was fluent but limited. He used short, simple sentences consisting of a few words. He could read and repeat simple sentences and name common objects. When asked to count to twenty, he counted to eleven and stopped. He could not count backward from ten or say the alphabet. Henry could not spontaneously recall my name, but when I said, “My name is Suzanne; do you know my last name?” he replied, “Corkin.” When I asked, “What do I do?” he responded, “Doctress.” It was heartwarming to see that Henry, even in the throes of dementia and other maladies, still had his sense of humor; when asked, “You’re not working anymore?” he replied, “No, that’s one thing I’m sure of.”
The positive news in 2007 was that Henry’s epilepsy was stable; Bickford staff members did not observe any grand mal seizures. He continued to be friendly, pleasant, and conversational, and was a passive participant in group activities but fell asleep if not stimulated. He often listened to music in the lounge and watched TV in his room.
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