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The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey

The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey Neurodegeneration REVIEW The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey 1 2,3 Martin R Turner, Michael Swash Nuffield Department of ABSTRACT problems, are complex. Sometimes, success follows Clinical Neurosciences, Recent advances in understanding amyotrophic lateral a chance observation, albeit usually one that arises University of Oxford, Oxford, sclerosis (ALS) have delivered new questions. from a hypothesis-driven approach to unlock the UK Disappointingly, the initial enthusiasm for transgenic basic pathobiology of the disorder. Here, we review Queen Mary University of London, London, UK mouse models of the disease has not been followed by the emergence of ALS as a disease, as both a clin- University of Lisbon, Lisbon, rapid advances in therapy or prevention. Monogenic ical and now a molecular syndrome, and emphasise Portugal models may have inadvertently masked the true their convergence. complexity of the human disease. ALS has evolved into a Correspondence to Dr Martin Turner, Nuffield multisystem disorder, involving a final common pathway THE DEFINITION OF A DISEASE Department of Clinical accessible via multiple upstream aetiological tributaries. As in many other diseases, Charcot’s first description Neurosciences, West Wing Nonetheless, there is a common clinical core to ALS, as Level 3, John Radcliffe was formulated in the context of his insightful clear today as it was to Charcot and others. We stress Hospital, Oxford OX3 9DU, clinical and pathological observations with his col- the continuing relevance of clinical observations amid USA; league Jean Cruveilhier (1791–1874), in a climate of martin.turner@ndcn.ox.ac.uk the increasing molecular complexity of ALS. novel ideas that arose from several European centres. Received 6 August 2014 Nevertheless, the description given in Charcot’s Revised 2 October 2014 1874 publication, in his ‘Tuesday Lectures’, and pre- Accepted 24 October 2014 saged in his earlier reports, set the scene for all subse- INTRODUCTION Published Online First quent investigations. Jean-Martin Charcot (1825–1893), in his comments 2 February 2015 Charcot’s genius consisted not only in describing of 1887, underestimated the complexity of the neu- the condition and its pathology, but also in naming rodegenerative disease he named “la sclérose it and separating it from other neurological condi- amyotrophique”: tions, especially those associated with muscular The diagnosis as well as the anatomy and physi- weakness and wasting. A name is the defining char- ology of the condition amyotrophic lateral sclerosis acteristic needed to facilitate universal understand- is one of the most completely understood condi- ing and recognition of a syndrome or, for example, tions in the realm of clinical neurology. in biology, of a species. An accepted nomenclature The history of amyotrophic lateral sclerosis (ALS) is also defines and limits a syndrome. Several of beset by misunderstandings and false beliefs. From its Charcot’s predecessors had also recognised the clin- 19th century beginnings, the path ahead has too often ical features of ALS, for example, the Edinburgh been considered straightforward, when in reality a surgeon Sir Charles Bell (1774–1842), Aran secure information base was lacking. The enormous (1817–1861) who probably first recognised pro- enthusiasm around the discovery, 20 years ago, of gressive muscular atrophy (PMA) and Cruveilhier genetic linkage between the superoxide dismutase himself. However, they failed in this essential (SOD1) gene and ALS now seems unjustified. SOD1 aspect; they did not name the disorder. Much intel- mutations are found in fewer than 2% of all cases, and lectual effort at this time was devoted to consider- these lack the molecular hallmark (TDP-43) common ing whether muscular wasting was due to disease of to nearly all the remainder. To ignore this group as an the muscle or nerve. The latter concept emerged outlying ALS ‘phenocopy’, however, seems equally only slowly as recognition of the importance of the misguided. Major investments in international multi- separate functions of the anterior and posterior centre clinical trials appear to have been based on rootlets of the spinal cord developed, following the Open Access poorly substantiated theoretical assumptions, fuelled independent work of Bell in Scotland and François Scan to access more free content by adesiresharedby all of us whointeractwiththose Magendie (1783–1855) in France. The British living with ALS, to do something rather than do anatomist Jacob Augustus Lockhart Clarke nothing. Unsurprisingly, they have thus far yielded dis- (1817–1880), working privately in a room at his appointingly negative results. home, contributed to this evolving concept in rela- Why then have there been so many false tion to studies of muscular dystrophy. In 1862, avenues? The answers are fundamental to extrapo- with Charles Bland Radcliffe (1822–1889), lating clinical observations into basic research and Lockhart Clarke described the clinical features and therapeutic trials and, eventually, into clinical prac- the pathological findings in “An important case of tice. Debate about the historical value and ongoing paralysis and muscular atrophy, with disease of the reliance on animal models continues more gener- nervous centres”, thus anticipating Charcot by To cite: Turner MR, 23 5 Swash M. J Neurol ally in Medicine. However, the factors leading to 3 years, but again without naming the disorder. Neurosurg Psychiatry success or failure in the development of ideas in There was a fundamental difference between the 2015;86:667–673. neuroscience, especially when applied to clinical approach taken to neurological investigation in Turner MR, et al. J Neurol Neurosurg Psychiatry 2015;86:667–673. doi:10.1136/jnnp-2014-308946 667 Neurodegeneration France and Britain in the last half of the 19th century. Charcot and cervical region, and atrophy of the bulbar motor nerves. Later, his followers were concerned with separating one disorder from he also noted relative sparing of the lumbosacral cord and conus another, for example, multiple sclerosis, epilepsy and Parkinson’s medullaris, with severe involvement of the brain stem. These important observations were acknowledged by Charcot in his disease and, especially, considering the role of psychological 1881 Lectures. Technique, as ever in science, is everything. disorders in neurology. In Britain, there was an emphasis on under- standing the phenomena of the disordered nervous system, rather Charcot noted that in ALS muscular wasting was usually than defining diseases per se, most clearly exemplified by the work more prominent in the upper limbs and rigidity was more prom- of John Hughlings Jackson (1835–1911) and his pupil David inent in the lower limbs. He described “fibrillary twitches of Ferrier (1843–1928). This emphasis on the biology of disease, muscles” (as had Lockhart Clarke), and the limitation of the dis- initially most frequently shared between British and German neu- order to the motor system. It was left to the greatest 19th rologists, has developed in modern times as a world-wide endeav- century classifier of neurological disease, William Richard our leading to modern neurophysiological and molecular Gowers (1845–1915), to suggest in his Manual of Diseases of neuroscientific studies. The resulting clinical insights led to a more the Nervous System that the several progressive disorders of robust definition of concepts such as rigidity and spasticity, delin- the motor system could be considered as syndromic variants. eation of particular patterns of weakness, recognition of the dysto- This was a view with which Charcot concurred, and which led nias, and an understanding of the different types of epilepsy. (Lord) Walter Russell Brain (1895–1966), in the 6th edition of Disordered mental and intellectual function was also studied as his influential Textbook of Neurology published in 1962, to use part of this late 19th century revolution, especially in subsequent the all-inclusive term Motor Neurone Disease, thus encompass- years by German scientists, such as von Monakow, Liepmann and ing the four main clinical subtypes: ALS (essentially limb-onset Goldstein. disease), progressive bulbar palsy, PMA, and progressive spastic paraparesis (now termed primary lateral sclerosis, PLS). Neither CLINICAL ASSESSMENT IN THE LATE 19TH CENTURY Gowers nor Brain regarded these terms as indicating mutually For Charcot and his contemporaries, the neurological examin- exclusive disorders. Rather, they thought of them as describing ation was far from its present form. Tendon reflexes, plantar clinical syndromes making up a single entity, the clinical features responses, detailed testing of muscle strength designed to check being determined by the relative distribution of pathological characteristic patterns of weakness, modality-based sensory change in the upper motor neuronal and lower motor neuronal testing, visual field examination, pupillary reflexes and tests of (UMN and LMN) systems, and its spatial distribution through muscle tone were either unknown or incompletely developed. the nervous system. Spasticity, as an increase in muscle tone or a disorder of stance Charcot and Gowers both recognised that ALS appeared to and gait, was recognised and well described by the paediatrician begin focally and spread through the body via contiguous neur- and orthopaedic surgeon William John Little (1810–1894) in onal systems, a clinical observation that was neglected until more the context of his description of clubfoot (from which he modern times. Indeed, spread of the disease through the neur- himself suffered) and cerebral palsy. axis has become a subject of contemporary re-investigation. Charcot referred in his lectures XI, XII and XIII to two pat- Gowers recognised three syndromes as related. The fourth, PLS, terns of motor system degeneration resulting in muscle atrophy was described by Wilhelm Heinrich Erb (1840–1921), although and weakness, which he termed protopathic and deuteropathic. in the early literature it is difficult to distinguish PLS from the The former consisted of muscular atrophy and weakness asso- familial spastic paraplegias. Gowers also noted that at autopsy ciated with degeneration of the anterior cornua of the spinal patients with the syndrome of PMA also showed degeneration of cord, varying in its extent at different levels. The latter term the corticospinal pathway, as was characteristic of ALS itself, an 10 11 was used to describe the combined degeneration of the anterior observation confirmed in more recent times. cornua with degeneration of the lateral columns of the cord, It is a central tenet of clinic-based prognostication in ALS that that is, the corticospinal tracts. However, Charcot did not cor- the rate of disease progression appears relatively fixed for an relate these pathological features with the pattern of the clinical individual. The past rate of progression generally does reflect disorder. In his Lectures, delivered at the Hôpital Salpêtriére in future deterioration, albeit with slightly more rapid progression the period 1858–1867, he stated “the role of alterations of the in disability noted at the start and end of the disease course. nerve cells themselves had not yet been elucidated”. However, Gowers was among the first to note this broad concept: “When he also stated “in amyotrophic lateral sclerosis, the symmetrical the progress at commencement is rapid, it usually continues lesions of the lateral columns, whence paralysis and contracture rapid, until the disease has attained a wide extent, although the result, is the first to make its appearance; while the alteration of acute local onset mentioned below may be followed by slow the anterior grey substance, with which muscular atrophy is con- extension. When it begins slowly, it is usually slow through- nected, would be a consecutive phenomenon”. (lecture XVl), a out”. He also identified “a special group” which is now recog- prescient observation in relation to the modern concept that the nised as the ‘flail arm’ variant of ALS, and uniformly slow in its motor cortex may be first affected in ALS. rate of progression (figure 1). It was also known to Gowers A similar problem confronted Lockhart Clarke, himself a that at autopsy in ALS there are always many preserved anterior pioneer of histological technique in studying the nervous horn cells; indeed, the process of motor neuronal loss is strik- 5 7 system, especially the spinal cord. With Radcliffe he noted that ingly patchy and multifocal, despite the more demarcated and without the use of his innovative techniques: the “ordinary and sequential spread of symptoms reported by patients. Typical of inefficient method of examining the nervous centres…would the inbuilt redundancy in most human biological systems, it has have resulted in ranking the case as one of simple muscular been estimated that one-third of large motor neurons must be atrophy”. He stated that the pathological changes “clearly and lost before there is visible atrophy. satisfactorily explained” the clinically evident muscular paralysis and atrophy. Lockhart Clarke’s description of the pathology is GENETIC AND ENVIRONMENTAL CONSIDERATIONS remarkably complete, including atrophy of the anterior roots, William Osler (1849–1919) described the first cases of heredi- particularly severe degeneration of the lateral columns in the tary PMA. Gowers also recognised the occurrence of familial 668 Turner MR, et al. J Neurol Neurosurg Psychiatry 2015;86:667–673. doi:10.1136/jnnp-2014-308946 Neurodegeneration Figure 1 Developments in cellular and clinical probes for amyotrophic lateral sclerosis (ALS) over 130 years. Lockhart Clarke’s hand-drawn atrophied anterior horn cells (top left) are contrasted with RNA foci (below, red dots) visualised within cortical neurons (nuclei, ∼5–10 m diameter, stained blue with DAPI) differentiated from induced pluripotent stem cells derived from patient with ALS fibroblasts. Gowers’ textbook contained detailed illustrations of a classical ‘flail arm’ variant of ALS with a head drop (top middle and right), contrasted with the white matter tractography of diffusion tensor MRI (bottom right, temporal lobe projection tracts shown in a cutaway coronal plane from the front). Cortical neuron image provided courtesy of Professor Kevin Talbot, University of Oxford. ALS, an observation that has assumed particular significance pathway (Clarke’s column), an afferent pathway that takes origin since the genetic revolution of modern times. Until recently, the in spinal cord segments among segmental neuronal pools that are literature on ALS was dominated by explorations of commonly effectively largely destroyed by the disease, is a sensory pathway assumed causative hypotheses, many derived from individual that is consistently affected in pathological studies of ALS. This patient experience. There are many early reports implicating may underlie the early symptom of impaired balance often trauma, but unbiased hospital record linkage studies have not reported by patients at diagnosis, though this has not been sys- supported an association. Lou Gehrig, an American baseball tematically studied. In addition, clinicians have long noted minor celebrity from the 1930s, is inextricably associated with the sensory and autonomic involvement in patients with ALS. disease in the USA. Various lifestyles, including unusual exercise Overlap between mild Parkinsonian features and ALS were well 19 20 27 regimes as in athletes, leisure-time activity, exposure to documented, and cross-over phenotypes have re-emerged 21 22 28 heavy work, soldiers in training, professional football within the spectrum of ALS linked to C9orf72 expansions. The 23 24 players and handedness have all provided seductive associa- Guamanian ALS-Parkinson’s-dementia complex represents an tions of uncertain significance. At present, the only established extreme, not least since it appears to be an acquired, non-genetic risk factors for the development of sporadic ALS, apart from form of the disease. assumed genetic risks, are increasing age, male gender and a The demonstration of ALS as a cerebral pathology involving very modest effect of smoking. An inverse relation between regions beyond the primary motor cortex emerged first from dietary intake of ω-3 fatty acids and risk of ALS is the most autopsy series. Cognitive impairment and occasional psychosis recent observation. were recognised among earlier descriptions of ALS (reviewed in ref. 30). The mid-1980s saw the emergence of a more subtle dysexecutive neuropsychological syndrome, followed by posi- ALS AS AN ANTERIOR BRAIN DISORDER tron emission tomography studies providing further evidence of The apparent symptomatic resistance of sensory and oculomotor 32 33 wide cerebral involvement in ALS. The finding of a shared neurons, along with those subserving sphincter functions, was neuropathological signature of cytoplasmic ubiquitinated noted in the earliest descriptions of ALS. The spinocerebellar Turner MR, et al. J Neurol Neurosurg Psychiatry 2015;86:667–673. doi:10.1136/jnnp-2014-308946 669 Neurodegeneration inclusions of the protein TDP-43 in ALS and frontotemporal and not all associated with ubiquitinated inclusions based on dementia (FTD) is probably the most important clinicomole- mutant TDP-43 aggregation (table 1). Mutations in TDP-43 itself cular discovery in ALS research to date. Overt FTD manifests in account for only a very small proportion of hereditary ALS, perhaps indicative of this gene’s fundamental role in develop- only 10–15% of patients with ALS, typically as an early 35 36 ment, so that most mutations are incompatible with embryogen- symptom, and is strongly associated with a G C hexanu- 4 2 cleotide repeat expansion in C9orf72. esis. It is axiomatic, therefore, that the common clinical The link between ALS and FTD represents an extension of phenotype, as instantly recognisable today as it was to Charcot, is ALS as a motor system disease to the frontal and temporal an end product of upstream cellular functions that may be lobes, themselves parts of the brain concerned with the expres- disrupted by a variety of mechanisms that appear disparate. sion of thought, planning, personality and speech, all aspects of These may include some or all of the excitotoxicity, neuroinflam- brain function that are strictly ‘motor’ in a wider sense. It lends mation and mitochondrial dysfunction, for which evidence has support to the view that ALS pathogenesis is in some way linked been independently gathered over recent decades (reviewed in to the neocortical evolutionary development of the anterior ref. 46). This observation is relevant to many genetically deter- motor brain. The phrase “what wires together, dies mined disorders, for example, mitochondrial disorders, limb- together” focuses on an idea that there may be discrete girdle and other muscular dystrophies, spinocerebellar degenera- systems whose boundaries have a role in defining the expression tions, and the familial spastic paraplegia syndromes. The syn- of degenerative processes. Thus, the long-held concept of drome of ALS is therefore a single disease in the clinical sense, ‘selective vulnerability’ of motor neurons has given way to a but a phenotype that results from a number of different, perhaps broader notion of ALS as a multisystem disease that may in part related biological abnormalities. Once initiated, or at some be defined by properties inherent to the motor system as well as tipping point in a finely balanced equilibrium throughout devel- the individual neuron. This can be understood as a conse- opment and early adult life, ALS appears to progress inexorably, quence of interconnected brain networks. Motor neurodegen- albeit at different rates among individuals. It therefore becomes eration may be a process selective at that level, rather than a important to consider the processes underlying and modulating disorder of susceptible neuronal subtypes. the common patterns of neuronal dysfunction and death in ALS, and not limit the research focus to the causative role of a mono- THREADS OF CONTINUITY BETWEEN CLINICAL genic mutation. AND MOLECULAR TAXONOMIES Studies of the C9orf72 G C hexanucleotide repeat mutation 4 2 Neurodegeneration seems to have been unmasked by the recent have opened a more precisely defined window into the mechan- marked increase in the average human lifespan. Indeed, in early ism of neuronal, and perhaps also astrocytic, degeneration in life, there may even be unrecognised biological advantages of ALS which might therefore apply to nearly 10% of all cases. mutations associated with neurodegenerative disease in the post- Repeat-associated non-ATG (RAN)-translated dipeptide pro- 42 43 47 48 reproductive years. Does sporadic ALS still exist as a valid ducts are toxic, driving neurodegeneration by expressing concept, and is all ALS due to inherited factors at some level? abnormalities in RNA-binding proteins, perhaps through the Significantly, no major environmental risk factors have so far formation of prion-like polymeric protein assemblies in the been discovered. At present, less than 10% of ALS in the UK cytosol. It is suggested that a slowly accumulating toxic effect population is associated with single gene mutations, the majority might account for the late onset and progressive course of the being expansions of the C9orf72 hexanucleotide repeat. disease (see commentary in ref. 49). Such dipeptide products Next-generation sequencing offers the hope of characterising have been detected postmortem in a 26-year-old with learning the multiple rare-variant signatures that may underlie perhaps difficulties but without dementia or motor symptoms, raising all of the remaining cases. the possibility of developmental as well as degenerative influ- Hereditary ALS and all the associated phenotypes are syn- ences for this expansion. However, to the clinician, the rela- dromes that can result from several different gene expressions tively abrupt onset and often rapid progression of ALS is and mutations, apparently specific to discrete protein pathways, striking, and provokes the concept of a tipping point or loss of Table 1 Molecular clues to the core historical clinical observations in ALS, and the current gaps in knowledge Core clinical observation Molecular clues Key knowledge gap Combined UMN and Ubiquitinated neuronal inclusions found in cortical and anterior horn Variable clinical expression of UMN versus LMN pathology, 34 54 LMN degeneration neuronal cell bodies including extremes (PMA, PLS) Variable site of symptom Higher proportion of bulbar-onset disease linked to C9orf72 G C Many examples, including: 4 2 72 73 onset expansions; and under-represented in SOD1 mutation-associated ALS Isolated bulbar variants; Reduced bulbar-onset with younger age; Lack of upper-limb onset in PLS (personal observation—MRT) Variable age at symptom FUS mutations linked to ALS with basophilic inclusions occur in young The apparent fall in incidence of ALS in those aged above age 85 75 76 onset adults years Familial cases C9orf72 G C expansions plus SOD1, TDP-43, and FUS mutations account Only 10% of all ALS cases carry one of these gene mutations 4 2 for two-thirds of those with a family history of ALS or FTD Variable rate of disease SOD1 ‘A4V’ (dominant, rapid) versus ‘D90A’ (typically recessive, slow) Typically relatively stable rates of disease progression in individual 78 12 79 progression mutations patients with ALS (familial and apparently sporadic) Cognitive involvement C9orf72 G C expansions strongly associated with ALS-FTD; Carriers of C9orf72 G C expansions within the same pedigree 4 2 4 2 37 80 Under-represented in SOD1 mutations may develop pure FTD instead of ALS ALS, amyotrophic lateral sclerosis; FTD, frontotemporal dementia; LMN, lower motor neuronal; PLS primary lateral sclerosis; PMA, progressive muscular atrophy; UMN, upper motor neuronal. 670 Turner MR, et al. J Neurol Neurosurg Psychiatry 2015;86:667–673. doi:10.1136/jnnp-2014-308946 Neurodegeneration tolerance for reasons yet to be discovered, possibly resulting same family showing different phenotypes, most recently high- lighted in those carrying G from an extraneous source acting on the basis of inbuilt suscep- C expansions in C9orf72, where 4 2 tibility. However, no such crucial external influence is currently relatively pure ALS and FTD may both occur. Such reasoning evident. has led to the suggestion that cytosolic protein aggregates in Whether RNA or protein mishandling will prove to be patho- ALS behave like prions, causing dysfunction by self-replicating genic themes common to all ALS is not yet certain, and clearly protein misfolding resembling the particular protein structure it raises a fundamental question as to why such profound distur- associated with the prion protein. Mutant SOD1 protein 60 61 bances in basic cellular functions can be tolerated for many appears to aggregate, and RNA protein aggregates have decades prior to the onset of symptoms, even accepting the also been reported to behave in this manner. Cell-to-cell trans- enormous functional reserve of the nervous system. Gowers’ mission may result from pinocytosis of protein aggregates or ‘abiotrophic doctrine’ hints that such fundamental aspects of micro-RNAs in the intercellular compartment, extruded from cellular function must presumably become derailed through damaged or dead cells via exosomes. Such hypotheses would interaction with as yet poorly-defined age-related phenomena. place vesicle trafficking as a strong candidate to be involved in ALS (and other neurodegenerative disorders) may represent a variable progression rates observed in ALS. loss of the cell’s capacity to safely handle proteins that have a Can anyone develop ALS? Given the apparent incomplete natural tendency to aggregate, or involve a loss of quality penetrance of genes associated with ALS, a more puzzling corol- control in protein manufacture that produces more aggregation- lary is whether some individuals will never develop the prone variants. Or, indeed, both processes may occur. A number of genetic mutation-driven cell stressors may be envisaged to accelerate such loss of tolerance, explaining why a SOD1 ‘A4V’ mutation can be just as aggressive to the motor system as a pathological C9orf72 hexanucleotide expansion. Why only the latter tends to involve cognitive impairment is not yet clear, but many scientists are focused on differential gene expression across brain regions. The process of trying to understand the biological basis for varying phenotypes within the syndrome is an ongoing challenge, and may require the use of unbiased, multifactorial, machine-learning approaches. ALS can be recognised as a syndrome with variable clinico- pathological involvement in three ‘compartments’: LMNs, UMNs and their frontotemporal connections. When the three are clinically coincident, it is associated with more rapidly pro- gressive disease. Conversely, long survival (10–20 years) has been linked to relatively pure UMN (PLS) or LMN (PMA) 54–56 involvement. Similarly, the median survival in ‘pure’ FTD is of the order of 10 years, suggesting a relative resistance to the spread between these three neuronal networks. Furthermore, the rate of disease progression measured according to the ALS Functional Rating Scale is largely constant over the central part of the disease course in any given patient with ALS. Whether these phenomena are a property of physical ‘wiring’, which might include a role for interneuronal circuitry or glial- neuronal interactions, is not yet clear. Much more needs to be understood concerning the potential transmission of dysfunc- tion from cell to cell, as this might lead to a practical approach to arresting the disease. Perhaps the extremes of PLS, PMA and FTD are the natural place to start this search (figure 2). ALS has the shortest median survival among neurodegenera- tive disorders. The relative infrequency of ALS may reflect the relative inaccessibility of the motor system to the protein ‘aggre- gopathies’ apparently common to all neurodegenerative dis- eases. Such a privileged status would seem likely within an evolutionary framework in which stable and reliable motor system function exerts a very large selection pressure. Once Figure 2 The cell versus the system in amyotrophic lateral sclerosis (after Talbot ). From the top: Genetic, environmental and stochastic breached, however, it may be that the descending motor system events influence events at the cellular and also the motor system level. (with the notable exception of oculomotor and sphincter path- These interact with each other to result in the core ALS syndrome of ways) is somehow more permissive to disease propagation, with mixed upper and lower motor neuron signs associated in the majority faster progression compared to more neocortically-centred neu- with relatively minor cognitive impairment. However, rarer pure upper rodegenerative processes. For example, primary FTD often motor neuron (primary lateral sclerosis, PLS), lower motor neuron shows signs of motor involvement at the end of a relatively long (progressive muscular atrophy, PMA) and frontotemporal dementia disease course. This is consistent with a connectivity-driven (FTD) variants are recognised. Moreover, these are all characteristically model rather than selective neuronal vulnerability, and might slower in progression, possibly reflecting the relative containment of hinge on an initial, stochastic, regionally-defined pathological pathology due to as yet unidentified ‘firewalls’ between neuronal ‘seed’. This would be consistent with affected members of the networks. Turner MR, et al. J Neurol Neurosurg Psychiatry 2015;86:667–673. doi:10.1136/jnnp-2014-308946 671 Neurodegeneration Contributors MRT and MS contributed to the conception, drafting and editing of condition, perhaps due to hitherto unexplored protective genes, the manuscript. MRT prepared the figures. limited expression of pathogenic genes across brain networks, Competing interests None. or a less permissive neuronal milieu on a larger scale. Cohort studies, using Gompertzian statistics, have suggested that there Provenance and peer review Commissioned; externally peer reviewed. might be a susceptible population, thus accounting for the Open Access This is an Open Access article distributed in accordance with the apparently reduced incidence of the disease among the very old, terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, while accepting that mortality at different age ranges reflects provided the original work is properly cited. See: http://creativecommons.org/ competition by different diseases. licenses/by/4.0/ At present, we cannot identify the onset of the disease other than by the patient’s observations of the onset of focal weakness and wasting, or mental change, but these onset features are REFERENCES vague in their timing, and must represent much earlier changes 1 Mackenzie IR, Bigio EH, Ince PG, et al. 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Amyotrophic lateral sclerosis and related conditions: a clinical repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal analysis. Arch Neurol Psychiat 1943;49:151–77. dementia: a cross-sectional study. Lancet Neurol 2012;11:323–30. Turner MR, et al. J Neurol Neurosurg Psychiatry 2015;86:667–673. doi:10.1136/jnnp-2014-308946 673 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Neurology Neurosurgery & Psychiatry British Medical Journal

The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey

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Abstract

Neurodegeneration REVIEW The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey 1 2,3 Martin R Turner, Michael Swash Nuffield Department of ABSTRACT problems, are complex. Sometimes, success follows Clinical Neurosciences, Recent advances in understanding amyotrophic lateral a chance observation, albeit usually one that arises University of Oxford, Oxford, sclerosis (ALS) have delivered new questions. from a hypothesis-driven approach to unlock the UK Disappointingly, the initial enthusiasm for transgenic basic pathobiology of the disorder. Here, we review Queen Mary University of London, London, UK mouse models of the disease has not been followed by the emergence of ALS as a disease, as both a clin- University of Lisbon, Lisbon, rapid advances in therapy or prevention. Monogenic ical and now a molecular syndrome, and emphasise Portugal models may have inadvertently masked the true their convergence. complexity of the human disease. ALS has evolved into a Correspondence to Dr Martin Turner, Nuffield multisystem disorder, involving a final common pathway THE DEFINITION OF A DISEASE Department of Clinical accessible via multiple upstream aetiological tributaries. As in many other diseases, Charcot’s first description Neurosciences, West Wing Nonetheless, there is a common clinical core to ALS, as Level 3, John Radcliffe was formulated in the context of his insightful clear today as it was to Charcot and others. We stress Hospital, Oxford OX3 9DU, clinical and pathological observations with his col- the continuing relevance of clinical observations amid USA; league Jean Cruveilhier (1791–1874), in a climate of martin.turner@ndcn.ox.ac.uk the increasing molecular complexity of ALS. novel ideas that arose from several European centres. Received 6 August 2014 Nevertheless, the description given in Charcot’s Revised 2 October 2014 1874 publication, in his ‘Tuesday Lectures’, and pre- Accepted 24 October 2014 saged in his earlier reports, set the scene for all subse- INTRODUCTION Published Online First quent investigations. Jean-Martin Charcot (1825–1893), in his comments 2 February 2015 Charcot’s genius consisted not only in describing of 1887, underestimated the complexity of the neu- the condition and its pathology, but also in naming rodegenerative disease he named “la sclérose it and separating it from other neurological condi- amyotrophique”: tions, especially those associated with muscular The diagnosis as well as the anatomy and physi- weakness and wasting. A name is the defining char- ology of the condition amyotrophic lateral sclerosis acteristic needed to facilitate universal understand- is one of the most completely understood condi- ing and recognition of a syndrome or, for example, tions in the realm of clinical neurology. in biology, of a species. An accepted nomenclature The history of amyotrophic lateral sclerosis (ALS) is also defines and limits a syndrome. Several of beset by misunderstandings and false beliefs. From its Charcot’s predecessors had also recognised the clin- 19th century beginnings, the path ahead has too often ical features of ALS, for example, the Edinburgh been considered straightforward, when in reality a surgeon Sir Charles Bell (1774–1842), Aran secure information base was lacking. The enormous (1817–1861) who probably first recognised pro- enthusiasm around the discovery, 20 years ago, of gressive muscular atrophy (PMA) and Cruveilhier genetic linkage between the superoxide dismutase himself. However, they failed in this essential (SOD1) gene and ALS now seems unjustified. SOD1 aspect; they did not name the disorder. Much intel- mutations are found in fewer than 2% of all cases, and lectual effort at this time was devoted to consider- these lack the molecular hallmark (TDP-43) common ing whether muscular wasting was due to disease of to nearly all the remainder. To ignore this group as an the muscle or nerve. The latter concept emerged outlying ALS ‘phenocopy’, however, seems equally only slowly as recognition of the importance of the misguided. Major investments in international multi- separate functions of the anterior and posterior centre clinical trials appear to have been based on rootlets of the spinal cord developed, following the Open Access poorly substantiated theoretical assumptions, fuelled independent work of Bell in Scotland and François Scan to access more free content by adesiresharedby all of us whointeractwiththose Magendie (1783–1855) in France. The British living with ALS, to do something rather than do anatomist Jacob Augustus Lockhart Clarke nothing. Unsurprisingly, they have thus far yielded dis- (1817–1880), working privately in a room at his appointingly negative results. home, contributed to this evolving concept in rela- Why then have there been so many false tion to studies of muscular dystrophy. In 1862, avenues? The answers are fundamental to extrapo- with Charles Bland Radcliffe (1822–1889), lating clinical observations into basic research and Lockhart Clarke described the clinical features and therapeutic trials and, eventually, into clinical prac- the pathological findings in “An important case of tice. Debate about the historical value and ongoing paralysis and muscular atrophy, with disease of the reliance on animal models continues more gener- nervous centres”, thus anticipating Charcot by To cite: Turner MR, 23 5 Swash M. J Neurol ally in Medicine. However, the factors leading to 3 years, but again without naming the disorder. Neurosurg Psychiatry success or failure in the development of ideas in There was a fundamental difference between the 2015;86:667–673. neuroscience, especially when applied to clinical approach taken to neurological investigation in Turner MR, et al. J Neurol Neurosurg Psychiatry 2015;86:667–673. doi:10.1136/jnnp-2014-308946 667 Neurodegeneration France and Britain in the last half of the 19th century. Charcot and cervical region, and atrophy of the bulbar motor nerves. Later, his followers were concerned with separating one disorder from he also noted relative sparing of the lumbosacral cord and conus another, for example, multiple sclerosis, epilepsy and Parkinson’s medullaris, with severe involvement of the brain stem. These important observations were acknowledged by Charcot in his disease and, especially, considering the role of psychological 1881 Lectures. Technique, as ever in science, is everything. disorders in neurology. In Britain, there was an emphasis on under- standing the phenomena of the disordered nervous system, rather Charcot noted that in ALS muscular wasting was usually than defining diseases per se, most clearly exemplified by the work more prominent in the upper limbs and rigidity was more prom- of John Hughlings Jackson (1835–1911) and his pupil David inent in the lower limbs. He described “fibrillary twitches of Ferrier (1843–1928). This emphasis on the biology of disease, muscles” (as had Lockhart Clarke), and the limitation of the dis- initially most frequently shared between British and German neu- order to the motor system. It was left to the greatest 19th rologists, has developed in modern times as a world-wide endeav- century classifier of neurological disease, William Richard our leading to modern neurophysiological and molecular Gowers (1845–1915), to suggest in his Manual of Diseases of neuroscientific studies. The resulting clinical insights led to a more the Nervous System that the several progressive disorders of robust definition of concepts such as rigidity and spasticity, delin- the motor system could be considered as syndromic variants. eation of particular patterns of weakness, recognition of the dysto- This was a view with which Charcot concurred, and which led nias, and an understanding of the different types of epilepsy. (Lord) Walter Russell Brain (1895–1966), in the 6th edition of Disordered mental and intellectual function was also studied as his influential Textbook of Neurology published in 1962, to use part of this late 19th century revolution, especially in subsequent the all-inclusive term Motor Neurone Disease, thus encompass- years by German scientists, such as von Monakow, Liepmann and ing the four main clinical subtypes: ALS (essentially limb-onset Goldstein. disease), progressive bulbar palsy, PMA, and progressive spastic paraparesis (now termed primary lateral sclerosis, PLS). Neither CLINICAL ASSESSMENT IN THE LATE 19TH CENTURY Gowers nor Brain regarded these terms as indicating mutually For Charcot and his contemporaries, the neurological examin- exclusive disorders. Rather, they thought of them as describing ation was far from its present form. Tendon reflexes, plantar clinical syndromes making up a single entity, the clinical features responses, detailed testing of muscle strength designed to check being determined by the relative distribution of pathological characteristic patterns of weakness, modality-based sensory change in the upper motor neuronal and lower motor neuronal testing, visual field examination, pupillary reflexes and tests of (UMN and LMN) systems, and its spatial distribution through muscle tone were either unknown or incompletely developed. the nervous system. Spasticity, as an increase in muscle tone or a disorder of stance Charcot and Gowers both recognised that ALS appeared to and gait, was recognised and well described by the paediatrician begin focally and spread through the body via contiguous neur- and orthopaedic surgeon William John Little (1810–1894) in onal systems, a clinical observation that was neglected until more the context of his description of clubfoot (from which he modern times. Indeed, spread of the disease through the neur- himself suffered) and cerebral palsy. axis has become a subject of contemporary re-investigation. Charcot referred in his lectures XI, XII and XIII to two pat- Gowers recognised three syndromes as related. The fourth, PLS, terns of motor system degeneration resulting in muscle atrophy was described by Wilhelm Heinrich Erb (1840–1921), although and weakness, which he termed protopathic and deuteropathic. in the early literature it is difficult to distinguish PLS from the The former consisted of muscular atrophy and weakness asso- familial spastic paraplegias. Gowers also noted that at autopsy ciated with degeneration of the anterior cornua of the spinal patients with the syndrome of PMA also showed degeneration of cord, varying in its extent at different levels. The latter term the corticospinal pathway, as was characteristic of ALS itself, an 10 11 was used to describe the combined degeneration of the anterior observation confirmed in more recent times. cornua with degeneration of the lateral columns of the cord, It is a central tenet of clinic-based prognostication in ALS that that is, the corticospinal tracts. However, Charcot did not cor- the rate of disease progression appears relatively fixed for an relate these pathological features with the pattern of the clinical individual. The past rate of progression generally does reflect disorder. In his Lectures, delivered at the Hôpital Salpêtriére in future deterioration, albeit with slightly more rapid progression the period 1858–1867, he stated “the role of alterations of the in disability noted at the start and end of the disease course. nerve cells themselves had not yet been elucidated”. However, Gowers was among the first to note this broad concept: “When he also stated “in amyotrophic lateral sclerosis, the symmetrical the progress at commencement is rapid, it usually continues lesions of the lateral columns, whence paralysis and contracture rapid, until the disease has attained a wide extent, although the result, is the first to make its appearance; while the alteration of acute local onset mentioned below may be followed by slow the anterior grey substance, with which muscular atrophy is con- extension. When it begins slowly, it is usually slow through- nected, would be a consecutive phenomenon”. (lecture XVl), a out”. He also identified “a special group” which is now recog- prescient observation in relation to the modern concept that the nised as the ‘flail arm’ variant of ALS, and uniformly slow in its motor cortex may be first affected in ALS. rate of progression (figure 1). It was also known to Gowers A similar problem confronted Lockhart Clarke, himself a that at autopsy in ALS there are always many preserved anterior pioneer of histological technique in studying the nervous horn cells; indeed, the process of motor neuronal loss is strik- 5 7 system, especially the spinal cord. With Radcliffe he noted that ingly patchy and multifocal, despite the more demarcated and without the use of his innovative techniques: the “ordinary and sequential spread of symptoms reported by patients. Typical of inefficient method of examining the nervous centres…would the inbuilt redundancy in most human biological systems, it has have resulted in ranking the case as one of simple muscular been estimated that one-third of large motor neurons must be atrophy”. He stated that the pathological changes “clearly and lost before there is visible atrophy. satisfactorily explained” the clinically evident muscular paralysis and atrophy. Lockhart Clarke’s description of the pathology is GENETIC AND ENVIRONMENTAL CONSIDERATIONS remarkably complete, including atrophy of the anterior roots, William Osler (1849–1919) described the first cases of heredi- particularly severe degeneration of the lateral columns in the tary PMA. Gowers also recognised the occurrence of familial 668 Turner MR, et al. J Neurol Neurosurg Psychiatry 2015;86:667–673. doi:10.1136/jnnp-2014-308946 Neurodegeneration Figure 1 Developments in cellular and clinical probes for amyotrophic lateral sclerosis (ALS) over 130 years. Lockhart Clarke’s hand-drawn atrophied anterior horn cells (top left) are contrasted with RNA foci (below, red dots) visualised within cortical neurons (nuclei, ∼5–10 m diameter, stained blue with DAPI) differentiated from induced pluripotent stem cells derived from patient with ALS fibroblasts. Gowers’ textbook contained detailed illustrations of a classical ‘flail arm’ variant of ALS with a head drop (top middle and right), contrasted with the white matter tractography of diffusion tensor MRI (bottom right, temporal lobe projection tracts shown in a cutaway coronal plane from the front). Cortical neuron image provided courtesy of Professor Kevin Talbot, University of Oxford. ALS, an observation that has assumed particular significance pathway (Clarke’s column), an afferent pathway that takes origin since the genetic revolution of modern times. Until recently, the in spinal cord segments among segmental neuronal pools that are literature on ALS was dominated by explorations of commonly effectively largely destroyed by the disease, is a sensory pathway assumed causative hypotheses, many derived from individual that is consistently affected in pathological studies of ALS. This patient experience. There are many early reports implicating may underlie the early symptom of impaired balance often trauma, but unbiased hospital record linkage studies have not reported by patients at diagnosis, though this has not been sys- supported an association. Lou Gehrig, an American baseball tematically studied. In addition, clinicians have long noted minor celebrity from the 1930s, is inextricably associated with the sensory and autonomic involvement in patients with ALS. disease in the USA. Various lifestyles, including unusual exercise Overlap between mild Parkinsonian features and ALS were well 19 20 27 regimes as in athletes, leisure-time activity, exposure to documented, and cross-over phenotypes have re-emerged 21 22 28 heavy work, soldiers in training, professional football within the spectrum of ALS linked to C9orf72 expansions. The 23 24 players and handedness have all provided seductive associa- Guamanian ALS-Parkinson’s-dementia complex represents an tions of uncertain significance. At present, the only established extreme, not least since it appears to be an acquired, non-genetic risk factors for the development of sporadic ALS, apart from form of the disease. assumed genetic risks, are increasing age, male gender and a The demonstration of ALS as a cerebral pathology involving very modest effect of smoking. An inverse relation between regions beyond the primary motor cortex emerged first from dietary intake of ω-3 fatty acids and risk of ALS is the most autopsy series. Cognitive impairment and occasional psychosis recent observation. were recognised among earlier descriptions of ALS (reviewed in ref. 30). The mid-1980s saw the emergence of a more subtle dysexecutive neuropsychological syndrome, followed by posi- ALS AS AN ANTERIOR BRAIN DISORDER tron emission tomography studies providing further evidence of The apparent symptomatic resistance of sensory and oculomotor 32 33 wide cerebral involvement in ALS. The finding of a shared neurons, along with those subserving sphincter functions, was neuropathological signature of cytoplasmic ubiquitinated noted in the earliest descriptions of ALS. The spinocerebellar Turner MR, et al. J Neurol Neurosurg Psychiatry 2015;86:667–673. doi:10.1136/jnnp-2014-308946 669 Neurodegeneration inclusions of the protein TDP-43 in ALS and frontotemporal and not all associated with ubiquitinated inclusions based on dementia (FTD) is probably the most important clinicomole- mutant TDP-43 aggregation (table 1). Mutations in TDP-43 itself cular discovery in ALS research to date. Overt FTD manifests in account for only a very small proportion of hereditary ALS, perhaps indicative of this gene’s fundamental role in develop- only 10–15% of patients with ALS, typically as an early 35 36 ment, so that most mutations are incompatible with embryogen- symptom, and is strongly associated with a G C hexanu- 4 2 cleotide repeat expansion in C9orf72. esis. It is axiomatic, therefore, that the common clinical The link between ALS and FTD represents an extension of phenotype, as instantly recognisable today as it was to Charcot, is ALS as a motor system disease to the frontal and temporal an end product of upstream cellular functions that may be lobes, themselves parts of the brain concerned with the expres- disrupted by a variety of mechanisms that appear disparate. sion of thought, planning, personality and speech, all aspects of These may include some or all of the excitotoxicity, neuroinflam- brain function that are strictly ‘motor’ in a wider sense. It lends mation and mitochondrial dysfunction, for which evidence has support to the view that ALS pathogenesis is in some way linked been independently gathered over recent decades (reviewed in to the neocortical evolutionary development of the anterior ref. 46). This observation is relevant to many genetically deter- motor brain. The phrase “what wires together, dies mined disorders, for example, mitochondrial disorders, limb- together” focuses on an idea that there may be discrete girdle and other muscular dystrophies, spinocerebellar degenera- systems whose boundaries have a role in defining the expression tions, and the familial spastic paraplegia syndromes. The syn- of degenerative processes. Thus, the long-held concept of drome of ALS is therefore a single disease in the clinical sense, ‘selective vulnerability’ of motor neurons has given way to a but a phenotype that results from a number of different, perhaps broader notion of ALS as a multisystem disease that may in part related biological abnormalities. Once initiated, or at some be defined by properties inherent to the motor system as well as tipping point in a finely balanced equilibrium throughout devel- the individual neuron. This can be understood as a conse- opment and early adult life, ALS appears to progress inexorably, quence of interconnected brain networks. Motor neurodegen- albeit at different rates among individuals. It therefore becomes eration may be a process selective at that level, rather than a important to consider the processes underlying and modulating disorder of susceptible neuronal subtypes. the common patterns of neuronal dysfunction and death in ALS, and not limit the research focus to the causative role of a mono- THREADS OF CONTINUITY BETWEEN CLINICAL genic mutation. AND MOLECULAR TAXONOMIES Studies of the C9orf72 G C hexanucleotide repeat mutation 4 2 Neurodegeneration seems to have been unmasked by the recent have opened a more precisely defined window into the mechan- marked increase in the average human lifespan. Indeed, in early ism of neuronal, and perhaps also astrocytic, degeneration in life, there may even be unrecognised biological advantages of ALS which might therefore apply to nearly 10% of all cases. mutations associated with neurodegenerative disease in the post- Repeat-associated non-ATG (RAN)-translated dipeptide pro- 42 43 47 48 reproductive years. Does sporadic ALS still exist as a valid ducts are toxic, driving neurodegeneration by expressing concept, and is all ALS due to inherited factors at some level? abnormalities in RNA-binding proteins, perhaps through the Significantly, no major environmental risk factors have so far formation of prion-like polymeric protein assemblies in the been discovered. At present, less than 10% of ALS in the UK cytosol. It is suggested that a slowly accumulating toxic effect population is associated with single gene mutations, the majority might account for the late onset and progressive course of the being expansions of the C9orf72 hexanucleotide repeat. disease (see commentary in ref. 49). Such dipeptide products Next-generation sequencing offers the hope of characterising have been detected postmortem in a 26-year-old with learning the multiple rare-variant signatures that may underlie perhaps difficulties but without dementia or motor symptoms, raising all of the remaining cases. the possibility of developmental as well as degenerative influ- Hereditary ALS and all the associated phenotypes are syn- ences for this expansion. However, to the clinician, the rela- dromes that can result from several different gene expressions tively abrupt onset and often rapid progression of ALS is and mutations, apparently specific to discrete protein pathways, striking, and provokes the concept of a tipping point or loss of Table 1 Molecular clues to the core historical clinical observations in ALS, and the current gaps in knowledge Core clinical observation Molecular clues Key knowledge gap Combined UMN and Ubiquitinated neuronal inclusions found in cortical and anterior horn Variable clinical expression of UMN versus LMN pathology, 34 54 LMN degeneration neuronal cell bodies including extremes (PMA, PLS) Variable site of symptom Higher proportion of bulbar-onset disease linked to C9orf72 G C Many examples, including: 4 2 72 73 onset expansions; and under-represented in SOD1 mutation-associated ALS Isolated bulbar variants; Reduced bulbar-onset with younger age; Lack of upper-limb onset in PLS (personal observation—MRT) Variable age at symptom FUS mutations linked to ALS with basophilic inclusions occur in young The apparent fall in incidence of ALS in those aged above age 85 75 76 onset adults years Familial cases C9orf72 G C expansions plus SOD1, TDP-43, and FUS mutations account Only 10% of all ALS cases carry one of these gene mutations 4 2 for two-thirds of those with a family history of ALS or FTD Variable rate of disease SOD1 ‘A4V’ (dominant, rapid) versus ‘D90A’ (typically recessive, slow) Typically relatively stable rates of disease progression in individual 78 12 79 progression mutations patients with ALS (familial and apparently sporadic) Cognitive involvement C9orf72 G C expansions strongly associated with ALS-FTD; Carriers of C9orf72 G C expansions within the same pedigree 4 2 4 2 37 80 Under-represented in SOD1 mutations may develop pure FTD instead of ALS ALS, amyotrophic lateral sclerosis; FTD, frontotemporal dementia; LMN, lower motor neuronal; PLS primary lateral sclerosis; PMA, progressive muscular atrophy; UMN, upper motor neuronal. 670 Turner MR, et al. J Neurol Neurosurg Psychiatry 2015;86:667–673. doi:10.1136/jnnp-2014-308946 Neurodegeneration tolerance for reasons yet to be discovered, possibly resulting same family showing different phenotypes, most recently high- lighted in those carrying G from an extraneous source acting on the basis of inbuilt suscep- C expansions in C9orf72, where 4 2 tibility. However, no such crucial external influence is currently relatively pure ALS and FTD may both occur. Such reasoning evident. has led to the suggestion that cytosolic protein aggregates in Whether RNA or protein mishandling will prove to be patho- ALS behave like prions, causing dysfunction by self-replicating genic themes common to all ALS is not yet certain, and clearly protein misfolding resembling the particular protein structure it raises a fundamental question as to why such profound distur- associated with the prion protein. Mutant SOD1 protein 60 61 bances in basic cellular functions can be tolerated for many appears to aggregate, and RNA protein aggregates have decades prior to the onset of symptoms, even accepting the also been reported to behave in this manner. Cell-to-cell trans- enormous functional reserve of the nervous system. Gowers’ mission may result from pinocytosis of protein aggregates or ‘abiotrophic doctrine’ hints that such fundamental aspects of micro-RNAs in the intercellular compartment, extruded from cellular function must presumably become derailed through damaged or dead cells via exosomes. Such hypotheses would interaction with as yet poorly-defined age-related phenomena. place vesicle trafficking as a strong candidate to be involved in ALS (and other neurodegenerative disorders) may represent a variable progression rates observed in ALS. loss of the cell’s capacity to safely handle proteins that have a Can anyone develop ALS? Given the apparent incomplete natural tendency to aggregate, or involve a loss of quality penetrance of genes associated with ALS, a more puzzling corol- control in protein manufacture that produces more aggregation- lary is whether some individuals will never develop the prone variants. Or, indeed, both processes may occur. A number of genetic mutation-driven cell stressors may be envisaged to accelerate such loss of tolerance, explaining why a SOD1 ‘A4V’ mutation can be just as aggressive to the motor system as a pathological C9orf72 hexanucleotide expansion. Why only the latter tends to involve cognitive impairment is not yet clear, but many scientists are focused on differential gene expression across brain regions. The process of trying to understand the biological basis for varying phenotypes within the syndrome is an ongoing challenge, and may require the use of unbiased, multifactorial, machine-learning approaches. ALS can be recognised as a syndrome with variable clinico- pathological involvement in three ‘compartments’: LMNs, UMNs and their frontotemporal connections. When the three are clinically coincident, it is associated with more rapidly pro- gressive disease. Conversely, long survival (10–20 years) has been linked to relatively pure UMN (PLS) or LMN (PMA) 54–56 involvement. Similarly, the median survival in ‘pure’ FTD is of the order of 10 years, suggesting a relative resistance to the spread between these three neuronal networks. Furthermore, the rate of disease progression measured according to the ALS Functional Rating Scale is largely constant over the central part of the disease course in any given patient with ALS. Whether these phenomena are a property of physical ‘wiring’, which might include a role for interneuronal circuitry or glial- neuronal interactions, is not yet clear. Much more needs to be understood concerning the potential transmission of dysfunc- tion from cell to cell, as this might lead to a practical approach to arresting the disease. Perhaps the extremes of PLS, PMA and FTD are the natural place to start this search (figure 2). ALS has the shortest median survival among neurodegenera- tive disorders. The relative infrequency of ALS may reflect the relative inaccessibility of the motor system to the protein ‘aggre- gopathies’ apparently common to all neurodegenerative dis- eases. Such a privileged status would seem likely within an evolutionary framework in which stable and reliable motor system function exerts a very large selection pressure. Once Figure 2 The cell versus the system in amyotrophic lateral sclerosis (after Talbot ). From the top: Genetic, environmental and stochastic breached, however, it may be that the descending motor system events influence events at the cellular and also the motor system level. (with the notable exception of oculomotor and sphincter path- These interact with each other to result in the core ALS syndrome of ways) is somehow more permissive to disease propagation, with mixed upper and lower motor neuron signs associated in the majority faster progression compared to more neocortically-centred neu- with relatively minor cognitive impairment. However, rarer pure upper rodegenerative processes. For example, primary FTD often motor neuron (primary lateral sclerosis, PLS), lower motor neuron shows signs of motor involvement at the end of a relatively long (progressive muscular atrophy, PMA) and frontotemporal dementia disease course. This is consistent with a connectivity-driven (FTD) variants are recognised. Moreover, these are all characteristically model rather than selective neuronal vulnerability, and might slower in progression, possibly reflecting the relative containment of hinge on an initial, stochastic, regionally-defined pathological pathology due to as yet unidentified ‘firewalls’ between neuronal ‘seed’. This would be consistent with affected members of the networks. Turner MR, et al. J Neurol Neurosurg Psychiatry 2015;86:667–673. doi:10.1136/jnnp-2014-308946 671 Neurodegeneration Contributors MRT and MS contributed to the conception, drafting and editing of condition, perhaps due to hitherto unexplored protective genes, the manuscript. MRT prepared the figures. limited expression of pathogenic genes across brain networks, Competing interests None. or a less permissive neuronal milieu on a larger scale. Cohort studies, using Gompertzian statistics, have suggested that there Provenance and peer review Commissioned; externally peer reviewed. might be a susceptible population, thus accounting for the Open Access This is an Open Access article distributed in accordance with the apparently reduced incidence of the disease among the very old, terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, while accepting that mortality at different age ranges reflects provided the original work is properly cited. See: http://creativecommons.org/ competition by different diseases. licenses/by/4.0/ At present, we cannot identify the onset of the disease other than by the patient’s observations of the onset of focal weakness and wasting, or mental change, but these onset features are REFERENCES vague in their timing, and must represent much earlier changes 1 Mackenzie IR, Bigio EH, Ince PG, et al. 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Journal

Journal of Neurology Neurosurgery & PsychiatryBritish Medical Journal

Published: Jun 2, 2015

Keywords: MOTOR NEURON DISEASE CLINICAL NEUROLOGY GENETICS MOLECULAR BIOLOGY PRION

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