Multidisciplinary ALS Clinics and the ALS Society of Canada

Arthur Hudson is widely considered the “Father of Canadian ALS”. His major contributions have withstood the test of time and those that he has mentored, and others have advanced his concepts. Arthur Hudson made four important contributions to ALS, and each is described in relevant sections of this review. The first major contribution was the formation of a multidisciplinary ALS clinic, the first of its kind in Canada and one of the first in the world. To our knowledge, the only dedicated ALS clinics in North America to predate the one started by Hudson were those developed by Forbes Norris in San Francisco, and Theodore (Ted) Munsat at the Tufts University, Boston. Hudson’s clinic at the University of Western Ontario, London, opened in 1977 serving much of the surrounding community in Ontario. ^{Reference Hudson1} It demonstrated that patients with ALS could be managed almost entirely as an outpatient with an expert multidisciplinary care team. Over a 7-year period after the clinic became operational, there was a decline in the annual mortality rates of those attending it. This occurred in the absence of a significant change in the incidence of ALS. Other Canadian clinics dedicated to ALS were started by Andrew Eisen, soon after arriving in Vancouver in 1980, and by Timothy Benstead in Nova Scotia shortly thereafter. The benefit that specialized clinics confer on ALS patients has been substantiated. ^{Reference Traynor, Alexander, Corr, Frost and Hardiman2} Thomas (Jock) Murray, working at the Dalhousie University, Nova Scotia, did not have a formalized multidisciplinary ALS clinic, but as early as 1974, he was centralizing care and observation of a significant number of ALS patients. ^{Reference Murray, Pride and Haley3}

Arthur Hudson’s second significant contribution was the establishment of the ALS Society of Canada as a not-for-profit charity registered on October 1, 1977. This predated the Motor Neurone Disease Association of Great Britain, which was registered in October 1979. Arthur Hudson was the founding Chairperson of the Medical Advisory Committee of ALS Canada and Patrick McGeer was a member of the committee. An initial proposal of the fledgling society was to establish a Nationwide Registry of ALS patients. This occurred in conjunction with the ALS Society of America (ALSA) through its liaison member to Canada, Barry Arnason, working in Chicago. Reciprocally Arthur Hudson was Canada’s liaison to ALSA. Andre Barbeau, Professor of Neurology at the University of Montreal, was chosen to oversee the project. Although his work was almost entirely devoted to Parkinson’s disease and dopamine and its pharmacology, he recognized that some ALS patients may have Parkinson’s dementia as a component of their disease. ^{Reference Barbeau4} Two decades later, positron emission studies in ALS confirmed there was indeed reduced dopamine activity in sporadic ALS. ^{Reference Takahashi, Snow, Bhatt, Peppard, Eisen and Calne5} Three years after ALS Canada was established, a provincial society, ALSBC, was organized in British Columbia and subsequently other provincial partners were organized throughout Canada, ultimately resulting in a unique collaborative Federation of Societies to provide provincial care locally and share obligations for research and advocacy nationally.

Investigating the Lower Motor Neurone in ALS

Prior to the end of the 1980s, investigative work in living ALS patients was uniformly limited to the lower motor neuron. As a result, ALS was classified as a neuromuscular disease. This erroneous nomenclature reflected the fact that only function and dysfunction of the lower motor neurone was readily accessible for study in vivo, primarily using electromyography. ^{Reference Marinacci and VonHagen6,Reference Daube7} Now, that it is accepted that ALS is a multisystem disorder, with prominent cortical involvement, it is untenable in the twenty-first century to continue to classify ALS as a neuromuscular disorder. ^{Reference van Es, Goedee, Westeneng, Nijboer and van den Berg8} It is should be classified as a neurodegenerative disease, as was suggested several decades ago by Eisen and Calne. ^{Reference Eisen and Calne9}

In 1971, Eisen and Karpati ^{Reference Eisen and Karpati10} described what at the time was a little recognized spontaneous activity in ALS, referred to as complex repetitive discharges. These are commonly recorded in this disease, but not unique to it. Most reflect ongoing motor axonal reinnervation. ^{Reference Posa, Niskiewicz, Emmer, Hanisch and Kornhuber11}

Shortly before Alan McComas moved to Hamilton, Ontario, from Newcastle, England, he described a methodology for measuring the number of motor units in human muscles. ^{Reference McComas, Fawcett, Campbell and Sica12} This marked the birth of decades of using motor unit estimates in ALS to measure disease progression and response to therapeutic agents in human and animal trials. ^{Reference Shefner, Cudkowicz, Zhang, Schoenfeld and Jillapalli13–Reference Shefner15} William (Bill) Brown with Nicholas (Nick) Jaatoul, at the University of Western Ontario, in London were among the first to apply the McComas method to investigate ALS. ^{Reference Brown and Jaatoul16,Reference Brown and Jaatoul17}

Corticomotoneuronal Studies in ALS

The third major contribution made by Hudson appeared in a rarely appreciated letter to the Lancet, written in 1988, ^{Reference Hudson and Kiernan18} entitled “Preservation of certain voluntary muscles in motorneurone disease”. It was proposed that cortical neurons may normally provide trophic support for neurons with which they make contact in the anterior horn and motor nuclei of the cranial nerves and, therefore, the primary pathology of motoneurons disease might be sought in the cortex rather than the spinal cord. The Lancet letter, essentially reiterated Charcot’s concept of ALS postulated over 100 years ago, ^{Reference Charcot19} and concurred with Andrew Eisen, who had been conceiving the primacy of the brain in ALS for some time. ^{Reference Eisen, Kim and Pant20} He proposed “the primary cell involved in amyotrophic lateral sclerosis (ALS) is the corticomotoneuron,” a term coined by Porter and Lemon. ^{Reference Porter and Lemon21} The spinal motoneuron becomes affected as a result of antegrade degenerative effects.

It only became feasible to study the upper motor neuron in ALS and related diseases, in vivo in the 1990s. Even in the late 1980s, MRI studies of ALS were sparse, limited to very few patients, and the results were mostly nonspecific. ^{Reference Goodin, Rowley and Olney22,Reference Iwasaki, Kinoshita, Ikeda and Takamiya23} In the late 1980s, transcranial magnetic stimulation (TMS) of the brain started to be used to investigate the upper motor neurone in ALS in the United Kingdom. ^{Reference Mills, Murray and Hess24} Andrew Eisen, in Vancouver, was the first in Canada to use the methodology to explore ALS. ^{Reference Eisen and Shtybel25,Reference Eisen, Shytbel, Murphy and Hoirch26} This was quickly followed by Bill Brown, who applied TMS to the study of PLS. ^{Reference Brown, Ebers, Hudson, Pringle and Veitch27} This legacy of pioneering in ALS has evolved in the present day to a national platform that uses these techniques to search for biomarkers and to approach heterogeneity of the disease alongside deep phenotyping and biofluid capture. ^{Reference Bharti, Khan and Beaulieu28}

Dementias and ALS

The fourth of Hudson’s major contributions was to bring to the fore the importance of dementia in ALS. Following the identification of the C9orf72 gene, shared by ALS and FTD, acceptance of dementia as a part of ALS spectrum of diseases, has become commonplace. ^{Reference Renton, Majounie and Waite29,Reference Snowden, Rollinson and Thompson30} However, 30 years prior to this, in a seminal paper published in Brain in 1981, ^{Reference Hudson31} Hudson proposed that dementia and Parkinsonism are associated with sporadic and familial ALS reflecting variants of classical ALS. Hudson’s interest in dementia and its association with ALS continued throughout his career. This ground-breaking work has continued through his student, and later colleague and close friend, Michael Strong, who has been recognized worldwide for his contributions as an ALS physician -scientist. In 2005, he initiated biannual workshops with international attendees, devoted to better understanding ALS-related dementias. This, alongside Hudson’s seminal and visionary work in ALS dementia, resulted in the ALS journal changing its name in 2013 to Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration.

Several years prior to Hudson’s paper in Brain, Morrison Finlayson, ^{Reference Finlayson and Martin32} a neuropathologist working at the Montreal General Hospital, together with Joseph Martin who later became the fourth Director of the Montreal Neurological Institute, before moving to the USA, described two cases of familial ALS associated with dementia. Some of the pathological features were common to those seen in Guamanian ALS. This intrigued John Steele, who at the time was also working at the Montreal General Hospital.

John Steele is probably best associated with the Steele–Richardson–Olszewski syndrome (progressive supranuclear palsy), ^{Reference Steele, Richardson and Olszewski33} which he described in 1964, while a neurology resident in Toronto. However, he has devoted much of his career to Guamanian ALS/PD also known as Lytico-Bodig disease. ^{Reference Steele and Guzman34} His initial publication on the condition was with Anthony (Tony) Guzman in 1987. After working at the Montreal General Hospital, Steele moved to reside in Guam, devoting his work to Lytico-Bodig disease. ^{Reference McGeer and Steele35} In 1990, Andrew Eisen, performed field studies on Guamanian ALS, using TMS. On return to Vancouver, employing positron emission tomography, it was shown that there were nigrostriatal lesions in Guamanian subjects with ALS, even in the absence of clinical Parkinsonism, exemplifying subclinical neuronal damage. ^{Reference Snow, Peppard and Guttman36} It was not until many years later that ALS was more commonly recognized as having a long presymptomatic period. ^{Reference Eisen, Kiernan, Mitsumoto and Swash37} An ALS symposium held in Vancouver in 1987, organized by Hudson and Eisen, emphasized the Guam story, ^{Reference Eisen and Hudson38} and was the basis of a book edited by Arthur Hudson in 1990. ^{Reference Hudson39} Other Canadians who contributed to the Vancouver meeting included Seung Kim, Jack Antel, John Steele, and Donald Calne.

Work with Tissue Culture

Seung Kim started working with cultured spinal cord neurones as early as 1972. ^{Reference Kim, O and Johnson40} In 1979, he started working on human tissue cultured spinal neurons, ^{Reference Silberberg and Kim41,Reference Kim, Warren and Kalia42} and the effect of aging. ^{Reference Kim43} At the Vancouver meeting he described work relating to the possible cytotoxic activity of ALS sera using human fetal spinal cord neuron cultures. ^{Reference Kim and Hudson44} No deleterious effect was found, contradicting an earlier study in which a high proportion of diluted serums of patients with ALS were toxic to the anterior horn cells of the mouse in tissue culture. ^{Reference Wolfgram and Myers45} In recent years, ALS sera have been shown to have variable effects on cultured cells. ^{Reference Texido, Hernandez and Martin-Satue46} Heather Durham commenced using tissue culture in connection with neurofilaments in 1986, ^{Reference Durham47} she subsequently used primary cultured neurones and transgenic animals expressing mutant genes linked to familial forms of neurodegenerative diseases. This enabled her to examine the interaction between expression of a predisposing gene and exposure to neurotoxic chemicals. ^{Reference Durham, O’Brien, Nalbantoglu and Figlewicz48} In 1987, while working with Tom Sears in London, UK, Charles Krieger performed whole-cell patch-clamp recordings on embryonic cultured spinal cord neurones. ^{Reference Fruns, Krieger and Sears49}

Neurofilaments and ALS

Neurofilaments are proteins selectively expressed in the cytoskeleton of neurones. Their potential utility has recently increased as advances have made it possible to measure levels in both the cerebrospinal fluid and blood. Increased levels are a marker of ongoing disease activity and decreased levels occur in response to therapy. ^{Reference Gafson, Barthelemy and Bomont50,Reference Gordon51} Pioneers of ALS in Canada have explored different aspects of neurofilaments. In 1968, Stirling Carpenter, working at the Montreal Neurological Institute, described frequent focal enlargement of axons in motor neurone disease. ^{Reference Carpenter52} Their absence was associated with severe neuronal loss in the spinal cord. ^{Reference Delisle and Carpenter53} Twenty years later, George Karpati, Stirling Carpenter, and Heather Durham suggested that the earliest abnormality in ALS was a progressive depletion of dendritic neurofilaments with consequent dendritic atrophy leading to shrinkage and eventual death of the perikaryon. ^{Reference Karpati, Carpenter and Durham54} George Karpati should be recognized for mentoring Heather Durham and Guy Rouleau, and later Angela Genge. These ALS physicians have all made major contributions and have become internationally recognized as leaders in the field.

Jean-Pierre Julien devoted his early years of work to neurofilament abnormalities. ^{Reference Julien, Mushynski, Duncan and Griffiths55} One of the co-authors of Julien’s first paper was Ian Duncan, one of the world’s best exemplars of veterinary research providing the basis for significant new insights into the understanding and treatment of human disease. In the early 1990s, both Denise Figlewicz and Guy Rouleau, collaborated with Julien working on neurofilamentous abnormalities in ALS. ^{Reference Figlewicz, Rouleau, Krizus and Julien56,Reference Figlewicz, Krizus and Martinoli57} Subsequently, working with transgenic ALS mouse models, Julien, proposed that neurofilament accumulation causes neurodegeneration by disrupting axonal transport, a mechanism that may account for the pathogenesis of ALS. ^{Reference Julien58}

Immunology and Inflammation in ALS

Neuroinflammation is a common pathological characteristic of neurodegeneration, including ALS. Features include activated CNS microglia and astroglia, proinflammatory peripheral lymphocytes, and macrophages. Genetic mutations linked to ALS (e.g. mutations in SOD1, TARDBP, and C9orf72) amplify neuroinflammation providing compelling evidence for immune dysregulation in the pathogenesis of ALS. ^{Reference Thonhoff, Simpson and Appel59,Reference Beers and Appel60} A large proportion of clinical trials in 2020 aim at targeting some aspect of the immune/inflammatory response. During the late 1960s and early 1970s, Patrick (Pat) and Edith (Edie) McGeer, working in the Kinsman Laboratory of Neurological Research, University of British Columbia, worked on varied aspects of neurochemical changes in aging, and diseases of the nervous system. ^{Reference McGeer, Fibiger, McGeer and Wickson61–Reference McGeer and McGeer64} Subsequently the McGeers’s research turned to inflammation and its role in neurodegenerations. They demonstrated a cell-mediated immune response identified immunohistochemically in ALS spinal cord and Alzheimer’s disease (AD) hippocampus. ^{Reference McGeer, McGeer, Kawamata, Yamada and Akiyama65}

Several years prior to the McGeer’s immunology-related work in neurodegeneration, Jack Antel while working with Barry Arnason, a Canadian, in Chicago, developed a keen interest in the immunity and ALS. ^{Reference Antel, Arnason, Fuller and Lehrich66–Reference Antel, Noronha, Oger and Arnason68} Jack, a Canadian, later moved to the Montreal Neurological Institute as Neurologist-in-Chief, where his main interest changed to multiple sclerosis. Joel Oger, another member of the Arnason group also had an early interest in ALS immunology. ^{Reference Lehrich, Oger and Arnason69} He moved to Vancouver, in the early 1980s, where his interest also changed to multiple sclerosis and then myasthenia gravis. Neil Cashman’s interest in ALS also commenced while he worked with Arnason and Antel in Chicago. ^{Reference Cashman, Gurney and Antel70} The collaboration led him to Montreal and Toronto before finally settling in Vancouver, where he continues to contribute as an ALS clinician-scientist.

Excitotoxicity

Excitotoxicity is not the newest and most spectacular hypothesis in the ALS field, but it is undoubtedly one of the most robust pathogenic mechanisms supported by an impressive amount of evidence. Moreover, the therapeutic efficacy of riluzole, which until recently was the only approved drug proven to slow disease progression in ALS, is most likely related to its anti-excitotoxic properties. ^{Reference Van Damme, Dewil, Robberecht and Van Den Bosch71} The excitotoxic hypothesis of neurodegeneration came to the fore in the early 1980s, and Pat and Edie McGeer turned their interest to this. ^{Reference McGeer and McGeer72} Somewhat later, Charles Krieger also worked on excitotoxicity. ^{Reference Allaoua, Chaudieu, Boksa, Perry, Krieger and Quirion73–Reference Krieger, Perry, Hansen, Mitsumoto and Honore75} Charles Krieger and Andrew Eisen collaborated on many publications, highlighted by a monograph on ALS. ^{Reference Eisen and Krieger76} When at the Montreal Neurological Institute, he got to know George Karpati, Heather Durham, and Guy Rouleau. It was there that he published his first ALS-related papers. ^{Reference Krieger and Melmed77,Reference Melmed and Krieger78}

Summary

The pathogenesis of the selective neuronal degeneration in ALS and its related disorders, in particular, FTD remains unsolved. Over the years, many pathogenic mechanisms have been proposed. Among others, these include oxidative stress, excitotoxicity, aggregate formation, inflammation, growth factor deficiency, abnormal RNA biology, protein disposal mechanisms, particularly autophagy, and neurofilament disorganization. Those pioneering work in ALS in Canada as described in this paper, contributed to many of the postulated causative hypotheses often leading the field at the time. In the 70s and 80s, a strong connection between research and the clinic drove much of this foundational work but, the current Canadian landscape does not support the development of the physician-scientist in the same way. Many of the ALS leaders in other countries are able to balance their clinical work with protected research time, providing a critical view of the discovery to treatment spectrum and there is a danger of these individuals being in short supply in Canada, particularly those dedicated to ALS. We write this in the sincere hope of encouraging some Canadians training in neurology to turn their enthusiasm and devotion to the ALS spectrum of disorders and remember the early days that paved the way for current discoveries through collaboration, intellectual curiosity, and dedication to a brighter day for the disease.