Robin Williams and Dementia with Lewy Bodies

Scattered throughout my childhood memories are many forms of Robin Williams; the mischievous genie in Aladdin, the loving father in Mrs. Doubtfire, the lost boy hidden within the serious man in Hook. His films served as a familiar blanket; one that I wrapped myself up in when I was sick and needed such warmth, curled up beside my father who shared my love for the soulful characters Robin Williams created. It wasn’t until I was older and beginning university that I came to appreciate his more serious acting repertoire. I watched Dead Poet’s Society because it is renowned for being sophisticated and intelligent – which suited the image I was trying to create of myself at the time. It moved me and my respect for the man only grew. The day after Robin Williams’ death was announced I watched Good Will Hunting for the first time and unashamedly cried my eyes out. A great actor, a man who spent his life making other people laugh, whose playful spark reminded me in many ways of my own dad, was gone. I never dreamed that only a year later, I would be one of many researchers working to understand a disease that changed his life: Dementia with Lewy Bodies (DLB).

What is Dementia with Lewy Bodies?

This is the question on many people’s’ lips since the revelation of Robin Williams’ diagnosis. DLB is a subtype of dementia, with approximately 15% of dementia patients’ symptoms falling under this characterization. This makes it the second most common dementia subtype, ranking just after Alzheimer’s Disease (AD) and above vascular dementia (VaD). Age of onset can be as early as 50 and rate of decline is approximately 10% per year. DLB gets its namesake from the presence of abnormal aggregates of protein called Lewy bodies in the cerebral cortex, brainstem and parts of the basal forebrain cholinergic system. These are thought to disturb neural processing and cause brain cells to die. Additionally, patients often present with AD pathology – such as amyloid plaques, which appear with similar density and distribution to that seen in AD. This affects symptomatology and contributes to the high rate of misdiagnosis in DLB.

What does Dementia with Lewy Bodies look like?

There is no easy answer to this question. DLB is notably heterogeneous and clinical profiling indicates it bears many similarities with both AD and Parkinson’s Disease (PD). Some core features have been identified however, including cognitive impairment in more than one domain, cognitive fluctuations, mild or spontaneous Parkinsonism and visual hallucinations. Unlike AD, memory impairment in DLB is not usually prominent early in the disease, with executive dysfunction and visuospatial difficulties more frequently reported at diagnosis. Patients’ fluctuations in cognition, mostly attentional, can occur on a day-to-day, hour-to-hour or minute-to-minute basis. Approximately 70% of patients experience parkinsonism symptoms such as bradykinesia, gait disturbances and limb rigidity. Visual hallucinations, while a hallmark of DLB, are only seen in two-thirds of patients, lending to the frequent misdiagnosis of AD. These hallucinations are described as colourful, vivid and three-dimensional mute animations. Depression is also common, with 40% of patients experiencing a major depressive episode. REM Sleep Behaviour Disorder predicts disease onset in a number of patients (as described in my previous blog) and may reflect underlying pathology as it rarely occurs with amyloidpathy or taupathy, marked features of AD.

Why is more research into Dementia with Lewy Bodies essential?

A focal issue with dementia is accurate clinical diagnosis; the dementia subtypes often appear similar in presentation which causes uncertainty for clinicians. DLB has a high rate of misdiagnosis, ranging from 34-65% of patients after post-mortem examination. Definitive conclusions cannot be drawn until autopsy, from which underlying pathological features can be discerned. Neuroimaging methods may assist diagnosis with studies indicating preservation of the hippocampal and medial temporal lobe regions distinguish DLB from AD. There are still gaping holes in the knowledge accumulated around this disorder and more research needs to be conducted in order to fill them, allowing better understanding of causes, pathophysiology, treatments and management of DLB. Of key importance here is establishing more stringent and robust methods of diagnosis as misdiagnosis can lead to sub-optimal or dangerous treatments. Central to this worry is incorrect pharmacological treatment; while patients generally have more positive responses to cholinesterase inhibitors than AD patients, neuroleptic drugs provided to ease psychiatric symptoms can cause extremely sensitive responses in 50-60% of DLB patients. Sudden onset or worsening of parkinsonism and impaired consciousness is reportedly due to this sensitivity and increases the risk of mortality 2-3 fold. In order to combat these issues, a focus on more extensive DLB research is needed.

While the news of Robin Williams’ death saddened me, the uncovering of his struggle with DLB struck another chord of sorrow. I empathized for him and his family’s experience of the progressive decline of his mind and body. But I recognised the solitary positive of this event; this hugely famous well-publicized figure that held a fond place in many people’s hearts had drawn attention to a relatively unknown disease. This brings with it the potential for increased public awareness and advocacy, improved services for carers and patients alike and promotion and encouragement for research into the dementia. Every cloud has a silver lining, even when it is the passing of a personal childhood hero.

References

McKEITH, I. G. (2002). Dementia with Lewy bodies. The British Journal of Psychiatry, 180(2), 144-147.

McKeith, I. G., Burn, D. J., Ballard, C. G., Collerton, D., Jaros, E., Morris, C. M., … & O’Brien, J. T. (2003, January). Dementia with Lewy bodies. InSeminars in clinical neuropsychiatry (Vol. 8, No. 1, pp. 46-57).

McKeith, I., Mintzer, J., Aarsland, D., Burn, D., Chiu, H., Cohen-Mansfield, J., … & Playfer, J. (2004). Dementia with Lewy bodies. The Lancet Neurology,3(1), 19-28.

Metzler-Baddeley, C. (2007). A review of cognitive impairments in dementia with Lewy bodies relative to Alzheimer’s disease and Parkinson’s disease with dementia. Cortex, 43(5), 583-600.

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Understanding Dementia: A Granddaughter’s Tale.

My grandmother died when I was eighteen years old, having been diagnosed with Alzehimer’s Disease several years beforehand. I did not see her much as her dementia started to progress; I believe it would have been a landmine of confusion for both of us. I was a young teenager, wrapped up in my own self-indulgences with no real understanding of the illness, and she was an elderly woman trapped in a disorientated and fragmented world, composed of shards of her former youth. As such, my memories of her during those years are few and far between. I can glimpse her sitting, slightly slouched on her old armchair in front of the fireplace, surrounded by ornamental dogs and gilded picture frames filled with faces of the family she cherished. She is wearing a white blouse with a navy jacket and matching skirt, slightly wrinkled flesh-coloured stockings and simple leather shoes. Her legs are crossed just below the knee. Her hair is white and slightly wavy and her face is weathered and marked with lines befitting of a woman who was never afraid of a hard day’s work. I perch on a tiny, cushioned stool against the wall and fidget. I don’t really know what is going on. I don’t really understand. My sister sits beside me with a smile straining across her face, as though it were battling through a more melancholic expression. She is eight years my senior and in this matter, infinitely more wise. My father stands by the mantelpiece, occasionally poking at the coal in the fire. He is still full of his usual mischievous humour, teasing my sister with sly remarks laden with wit and jovially conversing with visitors and carers, calling them all “kid” or “kiddo” regardless of age. Maybe he was putting on a brave face for us, for them, for himself. But my father is a rational man and his ability to accept serious matters with clarity and hoist a sea of troubles on his back without it breaking has always been remarkable. Every once in a while, my grandmother talks about unfamiliar people and places, while addressing my father with her husband’s name – the love of her life who died before I was even born. After the visit, we drive home. My sister and father chat in the front seats of the car, while I sit in the back and look out the window. My father has explained what’s wrong with my grandmother before, but I’m too young to comprehend.

The lost grandmother in the armchair was very different to my childhood memories of my grandmother. I called her “Nana”. Nana was a hardy woman with snowy hair and rosy cheeks. Every few Sundays, my father would collect me from my horse-riding lesson and take me to pick her up for a roast Sunday dinner. She would sit in the front of the car beside him and as we passed the church, she would ask him how he found mass that morning. Up to his old tricks, my father would spin imaginative tales about the priest’s illustrious sermon and my Nana would laugh, knowing rightly he hadn’t stepped inside the holy grounds. In my house, she would sit on the big brown leather settee in our sitting room and occasionally ask me questions, referring to me as “Baba”. In a way, I don’t have many recollections of her from those days either. However, I do have a firm memory of her strong presence, along with the feeling that no one could have pulled the wool over her eyes.

The year she died, I had just began my undergraduate degree in psychology. It was the beginning of winter and I had been updated unto her severely weakening state in the days previous. I was standing in a friend’s hallway on campus when I received the phone call to tell me she had passed away. I made arrangements to come home the next day on the bus and curled up in my friend’s bed and sobbed for my loss. A typical Irish wake was held, full of extended family, cups of tea, sandwiches, cake, laughter and reminiscing. I am one of the youngest cousins on my father’s side and therefore only familiar with a handful of the many relatives in attendance. Many of the unfamiliar ones exclaimed to my parents that they had not seen me since I was “this size” while gesturing to arbitrary but small distances from the ground, then peered at my face and wondered aloud as to which side of the family I looked like. No one seemed able to determine the answer (years later, it was concluded that I’m the image of my mother’s younger sister, after being mistook as her non-existent daughter several times on the same day). A joke spread throughout the gathering clan that my grandmother had timed her death as any hardworking woman would, with a wake to be held on the Friday, a funeral on the Sunday and everyone back in work for the Monday. My father shook well-wishers’ hands and slapped friends of the family on the back, all the while repeating “It was a happy release. It was a happy release”. I did not understand what that meant.

When it the time came to pay our respects to the body, all the grandchildren shuffled into the room with the open coffin in an orderly queue. I was near the end of the line. As those that had said their goodbyes passed me, I noticed several tears leaving tracks down their faces and heard the shaking breaths indicative of mournful crying. I steeled myself for my own physical manifestation of grief. But when I walked up to my grandmother and touched her clasped hands gently with my own and bestowed my parting kiss, not a single teardrop rolled down my cheek. It could not. This woman before me was not my childhood Nana, nor was she the lost grandmother in the armchair. This woman had twiglike arms and fragile skin pulled across a bony face, encircled by thin wisps of colourless hair. She was tiny and frail, and without a single ounce of fight left in her shrunken frame. This woman was alien to me. I walked away with my head bowed and lips pressed tightly together.

In the moment that I laid eyes on the last incarnation of my grandmother, a woman whose once-strong nature had forever been stamped into my mind, I understood. “It’s a happy release”. It was. My grandmother, my hearty Nana, had been set free from the imprisonment of her failing mind and her wasting body. I was finally comprehending what had been happening to her throughout all those years of illness. Alzheimer’s Disease and dementia weren’t just some form of extended forgetfulness. You weren’t simply mistaking someone’s name more often or losing personal belongings with increasing regularity. You were losing yourself, and with that, everyone else was losing you too. You were becoming a ghost.

At the end of this month, September 2015, I will officially be a doctoral student in neuroscience. The focus of my research is early diagnosis of dementia, with the expectation that this could lead to earlier implementation of interventions and a slower progression of the disorder. My hope is that this research and other complimentary investigations will help to extend the number of years that individuals with this crippling disease have to live their lives in health and happiness with true presence of mind. Indeed, there is already an outcry for more commitment, more time, and more money to help the many already afflicted. And the numbers continue to grow.

To my Nana, I hope that someday grandchildren will not have to understand what I now do. And I endeavour to help make it so.

C’mon Baby, Do The Locomotion: Gait Analysis as a a Diagnostic Tool for MCI and Dementia

Movement has long struck me as a funny thing. The general population regard it as a simple, automatic process and cast not another thought towards it; yet it is an incredibly complex synchronization of neuronal activity and muscular response. I will not ramble into the intricacies of this, but like many facets of the brain’s role in our daily life, we are still only scratching the surface of our understanding of such mechanisms. What I will bring to your attention is an exercise many of us engage in every day: walking.

It can easily be taken for granted that our locomotive abilities deplete with age: an elderly man’s stiff, heavy-footed shuffle shows only the thinnest ghost of a young boy’s playful, prancing step. This could be attributed to our muscular and general body function. We get old and we begin to feel all the aches and pains of living a long life. But we could imply that there is more to the change in our pace that the simple wear-and-tear the years have brought us. A variety of regions in the cerebral cortex influence our gait and the natural atrophy of our brain could change the manner and capacity of their function.

However, aging is not the only factor that changes our swagger. Neurological disorders, causing lesions to cerebral regions involved in gait, can become obvious through our walk. The most prominent example of this is the parkinsonism gait: small, shuffling steps and an overall slow pace. Indeed, in his book “Phantoms in the brain”, V.S. Ramachandran (2005) described an old professor of his instructing his medical class to diagnose Parkinson’s Disease with their eyes closed – simply by listening to the dragging sound of their feet as they walked. When we consider the cognitive components captured by locomotion, such an abnormality is not unfounded. Gait is directed by goals, thus is mediated by attentional circuits (Rochester, Galna, Lord & Burn, 2014). This involves frontal lobe activity, which is disrupted in Parkinson’s Disease due to the dysfunction of the basal ganglia. In the case of parkinsonism, velocity and stride length is predominately affected, but multiple sites within the cortico-basal ganglion-thalamic circuit can cause varying degrees of gait disturbances (Elble, 2007). As in Parkinson’s Disease, movement ability has been shown to decline years prior to the onset of cognitive impairments in the other common dementia subgroups (Montero-Odasso, Verghase, Beauchet & Hausdorff, 2012).

The Dynamic Relationship Between Gait and Cognition

That finding has opened a new area of research: the complementary relationship between gait and cognition. To discuss this, let us first examine the regions of the brain implicated in successful gait. We’ve already mentioned the frontal lobes’ role in attention, a fundamental component of locomotion. This area is also associated with executive function, which (depending on the paper) can describe a wide range of every day tasks: problem-solving, set-switching, working memory, reasoning, etc. These abilities are vital for engaging in our environments, allowing us to move through the world safely and efficiently. Without them, we are at risk of several locomotive problems, such as postural instability and falling (Montero-Odasso & Hachinski, 2014). This will be explained later in regards to the increasing demand accurate gait places on the cognitive resources of the diseased brain. The frontal subcortical networks controlling motor and cognitive abilities are located closely to one another, lending an explanation as to why white matter disease or frontal atrophy may simultaneously affect both gait and executive function. The temporal lobe also plays an important part in gait ability, due to its role in spatial navigation and memory (Annweiler, Beauchet, Bartha & Montero-Odasso, 2013). Unsteady and uncoordinated gait may result from lesions to the hippocampal area, as they would allow a deficit in the recall of the complex sequences of movement necessary for walking. Imaging studies have correlated medial temporal lobe atrophy with mild cognitive impairment (MCI; Annweiler et al., 2013). Lastly, it has been suggested that the parietal cortex’s integration of visuospatial, cognitive and motor information could have an impact on an individual’s gait.

Research into MCI’s relationship with gait has begun to spring up in the last number of years. MCI is described as a predementia state, with individuals developing either amnesic or other cognitive impairments  (Montero-Odasso, Oteng-Amoako, Speechley, Gopaul, Beauchet, Annweiler & Muir-Hunter, 2014). The current proposal behind the correlation in gait disturbances and cognitive failing is as follows: with age or disease, the automatic processes that the subcortical areas engage in to ensure smooth gait weaken, leading to a need for an increase in voluntary cortical mechanisms (Gillain, Warzee, Lekeu, Wojtasik, Maquet, Croisier… & Petermans, 2009). In essence, we begin to find it necessary to think about how we walk. Using this principle, our clever researchers have begun to develop a method in which to utilize gait analysis as a diagnostic tool for MCI. Lundin-Olsson’s (1997) seminal study “Stop walking when talking” introduced a new technique to predict falls: the dual task. This hypothesizes that walking while performing a secondary, cognitively engaging task will create competition between the brain’s resources, causing an interference effect. The modifications we must automatically make to our gait in order to navigate around our  environments are described as “costs” in relation to the diseased brain (Montero-Odasso & Hachinski, 2014). Hence, an individual who has yet to reveal cognitive deficits may reveal subtle gait impairments when asked to engage in a dual-task. These disturbances occur due to the cognitive stress placed on the neural networks mediating these tasks, and as such may be facilitated for the early prediction of MCI.

Gait Analysis and Dementia

These researchers are now beginning to apply these findings to the early prediction of dementia. This is a crucial area to develop, as dementia is becoming increasingly prevalent with our growing elderly population; approximately 8% of our over 65s are diagnosed with it, with as high as 35% of the over 85 age group reported to have it (Montero-Odasso et al., 2012). This not only takes a toll on the individuals suffering from dementia and their loved ones, it also places a rising monetary cost on society (Hurd, Martorell, Delavande, Mullen & Langa, 2013). Early diagnosis and treatment of dementia is currently the most feasible way forward to bring down both of these burdens. Gait analysis is a “cheap and cheerful” method in which to diagnose such diseases, as other techniques (such as neuroimaging) may not be suitable to individuals with limited resources (Verghese, Annweiler, Ayers, Barzilai, Beauchet, Bennett, … & Wang,2014). It is also quite applicable for early diagnosis, as gait disturbance has been observed up to 12 years prior to cognitive onset of dementia; this is certainly suitable for the most common sub-type, Alzheimer’s Disease, in which the neurodegeneration can begin as early as 20 years before obvious symptoms appear (Montero-Odasso et al., 2012). As it stands, the diagnostic measures are not overtly different from those from MCI; the employment of dual-task should sufficiently indicate an underlying cognitive disorder. What the literature is lacking is an accurate utilization of gait analysis in differentiating early signs of the dementia sub-groups. Some studies have shed light onto this matter by describing different failing gait characteristics for different dementias; a fine example is the growing body of evidence for motoric cognitive risk syndrome as a predictor of vascular dementia (Verghese et al., 2014). Another study has suggested that a deficit in gait rhythm could indicate underlying Alzheimer’s Disease pathology (Verghese, Wang,  Lipton, Holtzer,& Xue, X. 2007). Although this shows a start on the path forwards, we still have a long way to go before we find the answers we’re looking for.

The first steps into this treasure-trove of research are being made, and I, for one, am excited to see the kinds of hidden gems waiting to be discovered.

References

Annweiler, C., Beauchet, O., Bartha, R., & Montero-Odasso, M. (2013). Slow gait in MCI is associated with ventricular enlargement: results from the Gait and Brain Study. Journal of Neural Transmission, 120(7), 1083-1092.

Blakeslee, S. & Ramachandran, V.S. (2005). Phantoms in the Brain: Human nature and the architecture of the mind. London: Harper Perennial

Elble, R. J. (2007). Gait and dementia: moving beyond the notion of gait apraxia. Journal of neural transmission, 114(10), 1253-1258.

Gillain, S., Warzee, E., Lekeu, F., Wojtasik, V., Maquet, D., Croisier, J. L., … & Petermans, J. (2009). The value of instrumental gait analysis in elderly healthy, MCI or Alzheimer’s disease subjects and a comparison with other clinical tests used in single and dual-task conditions. Annals of physical and rehabilitation medicine, 52(6), 453-474.

Hurd, M. D., Martorell, P., Delavande, A., Mullen, K. J., & Langa, K. M. (2013). Monetary costs of dementia in the United States. New England Journal of Medicine, 368(14), 1326-1334.

Lundin-Olsson, L., Nyberg, L., & Gustafson, Y. (1997). “Stops walking when talking” as a predictor of falls in elderly people. The Lancet, 349(9052), 617.

Montero-Odasso, M., & Hachinski, V. (2014). Preludes to brain failure: executive dysfunction and gait disturbances. Neurological Sciences, 35(4), 601-604.

Montero-Odasso, M., Oteng-Amoako, A., Speechley, M., Gopaul, K., Beauchet, O., Annweiler, C., & Muir-Hunter, S. W. (2014). The motor signature of mild cognitive impairment: results from the Gait and Brain Study. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, glu155.

Montero‐Odasso, M., Verghese, J., Beauchet, O., & Hausdorff, J. M. (2012). Gait and cognition: a complementary approach to understanding brain function and the risk of falling.  Journal of the American Geriatrics Society, 60(11), 2127-2136.

Rochester, L., Galna, B., Lord, S., & Burn, D. (2014). The nature of dual-task interference during gait in incident Parkinson’s disease. Neuroscience, 265, 83-94.

Verghese, J., Annweiler, C., Ayers, E., Barzilai, N., Beauchet, O., Bennett, D. A., … & Wang, C. (2014). Motoric cognitive risk syndrome Multicountry prevalence and dementia risk. Neurology, 83(8), 718-726.

Verghese, J., Wang, C., Lipton, R. B., Holtzer, R., & Xue, X. (2007). Quantitative gait dysfunction and risk of cognitive decline and dementia.Journal of Neurology, Neurosurgery & Psychiatry, 78(9), 929-935.