Amyotrophic Lateral Sclerosis (ALS), also referred to as motor neuron disease, is a progressive disease affecting both upper and lower motor neurons. According to the El Escorial criteria  and its revisions [2-5], diagnosis is largely based on clinical and electrophysiological evidence of motor neuron dysfunction to the exclusion of other motor disorders. However, ALS may be conceptualized as a collection of disorders with numerous phenotypic variants, each with its own implications for prognosis and treatment [6-7]. One such variant is ALS with comorbid frontotemporal dementia (FTD).
One third to one half of individuals with ALS exhibit cognitive impairment in at least one domain, and approximately 15% meet criteria for FTD [8-9]. It is unlikely that ALS with FTD represents a discrete diagnostic category; rather, cognitive and behavioural symptoms that are characteristic of FTD appear to fall on a continuum in ALS . Among individuals with ALS, common cognitive symptoms include executive dysfunction (e.g., impaired verbal fluency, complex attention, cognitive flexibility) and to a lesser degree, language and memory impairment [10-12]. Behavioural abnormalities may also be prominent, including apathy, irritability, disinhibition, and impaired social cognition [12-14]. Based on the observation that individuals without dementia may exhibit clinically meaningful cognitive and behavioural changes, Strong and colleagues  proposed a classification system for frontotemporal syndromes in ALS, which characterizes syndromes that meet criteria for a dementia diagnosis [ALS-FTD and ALS-comorbid dementia (non-FTD)] as well as those that do not meet full criteria but represent significant impairments (ALS-behavioural impairment and ALS-cognitive impairment).
In addition to cognitive and behavioural symptomatology, ALS and FTD share common neuropathological features. In neuroimaging studies, cognitively-impaired individuals with ALS exhibit patterns of atrophy and hypometabolism/hypoperfusion in frontotemporal regions that are comparable to those observed in FTD [13,16-18]. Even in the absence of overt dementia, large-scale abnormalities in cortical thickness and functional connectivity have been detected in ALS [19-20]. In terms of pathogenesis, some genetic mutations and other biomarkers have been implicated in both ALS and FTD . For example, in 2006, Neumann and colleagues  discovered that TAR DNA-binding protein 43 (TDP-43) was the major disease protein in both ALS and FTD. In 2011, mutations of the C9ORF72 gene were shown to explain familial cases of co-occurring ALS and FTD linked to chromosome 9 [22-23]. These and other discoveries are further evidence of the disease continuum that accounts for ALS and FTD concordance.
Detection of cognitive impairment in individuals with ALS is essential for treatment planning. Individuals with ALS-FTD demonstrate lower rates of compliance with nutritional and respiratory interventions compared to individuals with ALS alone . Since these interventions are administered in advanced stages of the disease to prolong survival, noncompliance likely contributes to the shorter survival times observed among individuals with ALS-FTD compared to ALS alone [24-25]. Among individuals without FTD, executive impairment may also predict shorter survival in ALS, whereas more subtle or non-executive impairments are not thought to affect survival [25-26]. Greater cognitive impairment in ALS has also been linked to increased caregiver burden . Finally, capacity in healthcare decision-making is an important consideration in ALS, especially as it relates to end-of-life decisions. Given that cognitive symptoms often precede motor symptoms in ALS-FTD , it may be prudent to establish advance directives at the earliest signs of cognitive decline before decision-making becomes affected and speech/motor disturbances hinder communication. In light of these challenges, early neuropsychological assessment should be undertaken in order to best prepare patients, caregivers, and clinicians for the road ahead.
Beeldman, E., Raaphorst, J., Klein Twennaar, M., Govaarts, R., Pijnenburg, Y. A. L., de Haan, R. J., … Schmand, B. A. (2018). The cognitive profile of behavioural variant FTD and its similarities with ALS: A systematic review and meta-analysis. Journal of Neurology, Neurosurgery & Psychiatry. Advance online publication. http://doi.org/10.1136/jnnp-2017-317459
Abstract: Approximately 30% of patients with amyotrophic lateral sclerosis (ALS) have cognitive impairment and 8%–14% fulfil the criteria for behavioural variant frontotemporal dementia (bv-FTD). The cognitive profiles of ALS and bv-FTD have been reported to be comparable, but this has never been systematically investigated. We aimed to determine the cognitive profile of bv-FTD and examine its similarities with that of ALS, to provide evidence for the existence of a cognitive disease continuum encompassing bv-FTD and ALS. We therefore systematically reviewed neuropsychological studies on bv-FTD patients and healthy volunteers. Neuropsychological tests were divided in 10 cognitive domains and effect sizes were calculated for all domains and compared with the cognitive profile of ALS by means of a visual comparison and a Pearson’s r correlation coefficient. We included 120 studies, totalling 2425 bv-FTD patients and 2798 healthy controls. All cognitive domains showed substantial effect sizes, indicating cognitive impairment in bv-FTD patients compared to healthy controls. The cognitive domains with the largest effect sizes were social cognition, verbal memory and fluency (1.77–1.53). The cognitive profiles of bv-FTD and ALS (10 cognitive domains, 1287 patients) showed similarities on visual comparison and a moderate correlation 0.58 (p=0.13). When social cognition, verbal memory, fluency, executive functions, language and visuoperception were considered, i.e. the cognitive profile of ALS, Pearson’s r was 0.73 (p=0.09), which raised to 0.92 (p=0.03), when language was excluded in this systematic analysis of patients with a non-language subtype of FTD. The cognitive profile of bv-FTD consists of deficits in social cognition, verbal memory, fluency and executive functions and shows similarities with the cognitive profile of ALS. These findings support a cognitive continuum encompassing ALS and bv-FTD.
(Lecture) Pathology and current molecular classification of ALS/FTD
Presenter: Dr. Tibor Hortobagyi, Department of Neuropathology, University of Debrecen, Hungary
Dr. Hortobagyi provides a summary of neuropathological findings in ALS from the first candidate disease proteins and genetic mutations to the current state of knowledge, noting common biomarkers of ALS and FTD. This video begins with a general discussion of the importance of neuropathological investigation for the classification of neurodegenerative disorders.
(Seminar) Caregiver education program for ALS-FTD
Presenter: Dr. Susan Walsh, ALS Association of Greater Philadelphia, USA
This is the first part of a three-part educational seminar for caregivers of individuals with ALS and FTD. In this segment, Dr. Walsh provides background information on ALS and FTD. The second and third segments (also available on Youtube) describe practical strategies with respect to behaviour management and problem solving.
(Handout) ALS & Cognitive Changes
Publisher: ALS Society of Canada
This handout provides basic information on cognitive and behavioural changes in ALS. In the past, individuals with ALS and their caregivers have reported feeling under-informed about cognitive changes , so a handout such as this one can be helpful in starting important conversations about what to expect.
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Tsermentseli, S., Leigh, P. N., & Goldstein, L. H. (2012). The anatomy of cognitive impairment in amyotrophic lateral sclerosis: More than frontal lobe dysfunction. Cortex, 48(2), 166–182. http://doi.org/10.1016/j.cortex.2011.02.004
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