Elsevier

The Lancet Neurology

Volume 6, Issue 11, November 2007, Pages 994-1003
The Lancet Neurology

Review
Cognitive impairment in amyotrophic lateral sclerosis

https://doi.org/10.1016/S1474-4422(07)70265-XGet rights and content

Summary

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that has sporadic and inherited forms. ALS is the most common neurodegenerative disorder of young and middle-aged adults, and few treatments are available. Although the degeneration predominantly affects the motor system, cognitive and behavioural symptoms have been described for over a century, and there is evidence that ALS and frontotemporal dementia overlap clinically, radiologically, pathologically, and genetically. Cognitive decline in ALS is characterised by personality change, irritability, obsessions, poor insight, and pervasive deficits in frontal executive tests. This presentation is consistent with the changes to character, social conduct, and executive function in frontotemporal dementia. We highlight genetic, imaging, and neuropathological evidence that non-motor systems are affected in ALS and explain the importance of recent discoveries. We review studies of cognitive impairment in ALS and common neuropsychological test results. We also provide advice about clinical assessment of frontotemporal dysfunction in patients with ALS, and suggest future research. Understanding of cognitive impairment in ALS will improve care for patients and their families and provide valuable insights into the pathogenesis of neurodegeneration.

Introduction

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that has age-dependent onset and duration. Although the causes of ALS are not well understood, recent studies support the view that ALS is a complex genetic disorder.1 About 10% of ALS cases are familial, with a Mendelian pattern of inheritance. A fifth of these cases are associated with mutations in the superoxide dismutase 1 gene (SOD1).2 The remaining 90% of ALS cases are classed as sporadic, although there is accumulating evidence that subpopulations of patients with sporadic ALS have common inherited susceptibility genes.1, 3, 4

ALS was traditionally believed to spare cognitive functions, but is now known to involve a range of cognitive impairments. Most patients with ALS have mild cognitive impairment with subtle executive deficits, and 5% have a clinical subtype of frontotemporal lobar degeneration (FTLD) called frontotemporal dementia.5, 6 FTLD, which was originally described as Pick's disease, is the second most common cause of progressive cognitive impairment after Alzheimer's disease. The three forms of FTLD were defined by consensus criteria in 1998 (table 1).7 The form most frequently described in patients with ALS is frontal variant frontotemporal dementia (fvFTD); the other two forms are non-fluent progressive aphasia, which is characterised by language impairment, and semantic dementia, which is characterised by loss of conceptual knowledge.

The behavioural changes associated with fvFTD differ according to which neuroanatomical pathways are most severely affected.8 Some patients become disinhibited, fatuous, purposelessly overactive, and easily distracted, with socially inappropriate behaviour and little concern for others. Pathological changes in these patients are confined to orbitomedial frontal and anterior temporal regions. Other patients become bland, apathetic, inert, mentally rigid, and perseverative, and lack volition and mental effort. In these patients, pathological changes extend throughout the frontal lobes, including the dorsolateral frontal cortex. A third group of patients presents with stereotyped, ritualistic behaviour that is associated with substantial changes to the striatum. These patients also have variable cortical involvement, often with pathology of the temporal lobe rather than the frontal lobe. In ALS, the most common recognised form of cognitive impairment is frontal dysexecutive syndrome. This syndrome refers most closely to the second of the three aforementioned groups.

Section snippets

A possible spectrum of ALS and dementia

Although ALS is predominantly a disease of motor system degeneration, cognitive and behavioural symptoms have been described for over a century, and an association between ALS and frontal lobe dementia was postulated as early as 1932.9 Many authors have since suggested that ALS and frontotemporal dementia form a clinical and pathological spectrum. This idea remains controversial, but there is no doubt that ALS and frontotemporal dementia have clinical, radiological, pathological, and genetic

Patterns of cognitive impairment in ALS

Although there is a clear link between some forms of ALS and frontotemporal dementia, the frequency, severity, and progression of cognitive impairment in otherwise classic ALS remain unclear. The most consistently reported cognitive changes in ALS relate to dysfunction in components of the executive system (eg, verbal fluency and attention), whereas abnormalities in memory and language are less well characterised. Table 3 summarises some of these findings.

Incidence and prevalence of cognitive decline

The exact phenotype and natural history of impaired cognition in ALS are unclear. The confusion lies partly in the source of patients: those who attend a behavioural clinic and later have evidence of motor system degeneration might differ from those who attend a neuromuscular clinic and later develop impaired cognition. Thus, reports of the frequency, severity, and type of cognitive impairment in ALS patients vary substantially. Methods used to assess cognitive impairment have also differed,

Does cognitive impairment form a continuum?

Clinical evidence that cognitive dysfunction in ALS forms a continuum, from mild impairment to frontotemporal lobar dementia,80 remains weak. Most patients with ALS do not have overt clinical features of dementia; there is evidence that such patients have a subtle impairment of frontal executive functions that include verbal fluency and attention, but visuospatial abilities and psychomotor speed are usually preserved. Whether some of these neuropsychological changes are a consequence of

Optimum methods for examination

There is currently no consensus among researchers on the definition and measurement of cognitive impairment in ALS,50 on the psychometric methods used to assess patients, or on the nature of the cognitive deficits associated with frontotemporal dementia. However, working guidelines for optimum cognitive assessment in patients with ALS have been suggested by Strong and colleagues,82 and more conclusive consensus documents are due to be published as a result of discussions at the Second

Does cognitive impairment matter?

The potential clinical implications of cognitive impairment in patients with classic ALS have major importance. Problems with judgment, attention, inhibition, and generation of responses should be taken into account when patient care is planned. For example, deteriorating cognitive or executive function can compromise capacity to make decisions about health care or financial circumstances, and the ability to engage competently in end-of-life decisions. Cognitive impairment can also reduce

What to do in the clinic

Currently, the frequency of impaired cognitive function in patients with typical ALS cannot be established definitively, and formal mechanisms to evaluate the significance of clinical findings are not in place. Clinicians should be aware that patients with ALS might have cognitive impairment, and that patients who attend behavioural neurology clinics might well have anterior horn cell dysfunction. Clinicians who work with patients who have ALS should be alert to changes in character or

Future research

Although evidence suggests that ALS and FTLDU are different clinical manifestations of the same neurodegenerative disorder, the nature of cognitive impairment in ALS is still not fully understood. Major difficulties are that the degree and progression of cognitive impairment have not been well characterised within a population-based cohort, and that the clinical boundary between patients with ALS who have dementia and those who do not (ie, the distinction between progressive dementia and

Search strategy and selection criteria

Only articles published in English were reviewed. Data were searched during a 4 month period between March, 2007, and June, 2007, on PubMed with the following keywords: “amyotrophic lateral sclerosis”, “motor neuron disease”, “frontotemporal dementia”, “cognitive impairment”, “behaviour”, “pathology”, and “genetics”. Articles were also identified through searches of the references of these articles. Additionally, many articles were chosen from the files of the authors. Abstracts and

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