Amyotrophic Lateral Sclerosis with Frontotemporal Dementia

Cure America of Anosognosia

Amyotrophic Lateral Sclerosis with Frontotemporal Dementia

Contributor: Daniella Ladowski, M.Sc., University of Western Ontario (Doctoral Candidate)
Topic overview:
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 [1] 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 [6]. 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 [15] 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 [12]. For example, in 2006, Neumann and colleagues [21] 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 [24]. 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 [27]. 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 [26], 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.
Highlighted abstract:
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.
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.
Other media/resources:
(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 [28], so a handout such as this one can be helpful in starting important conversations about what to expect.
Further Reading:
Ferrari, R., Kapogiannis, D., D. Huey, E., & Momeni, P. (2011). FTD and ALS: A tale of two diseases. Current Alzheimer Research8(3), 273–294.
Giordana, M. T., Ferrero, P., Grifoni, S., Pellerino, A., Naldi, A., & Montuschi, A. (2011). Dementia and cognitive impairment in amyotrophic lateral sclerosis: A review. Neurological Sciences32(1), 9–16.
Goldstein, L. H., & Abrahams, S. (2013). Changes in cognition and behaviour in amyotrophic lateral sclerosis: Nature of impairment and implications for assessment. The Lancet Neurology12(4), 368–380.
Lillo, P., & Hodges, J. R. (2010). Cognition and behaviour in motor neurone disease. Current Opinion in Neurology23(6), 638–642.
Tsermentseli, S., Leigh, P. N., & Goldstein, L. H. (2012). The anatomy of cognitive impairment in amyotrophic lateral sclerosis: More than frontal lobe dysfunction. Cortex48(2), 166–182.
1.Brooks, B. R. (1994). El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Journal of the Neurological Sciences124, 96–107.
2.Miller, R. G., Munsat, T. L., Swash, M., & Brooks, B. R. (1999). Consensus guidelines for the design and implementation of clinical trials in ALS. Journal of the Neurological Sciences169(1–2), 2–12.
3.Brooks, B. R., Miller, R. G., Swash, M., & Munsat, T. L. (2000). El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis1(5), 293–299. Carvalho, M., Dengler, R., Eisen, A., England, J. D., Kaji, R., Kimura, J., … Swash, M. (2008). Electrodiagnostic criteria for diagnosis of ALS. Clinical Neurophysiology119(3), 497–503.
5.Ludolph, A., Drory, V., Hardiman, O., Nakano, I., Ravits, J., Robberecht, W., & Shefner, J. (2015). A revision of the El Escorial criteria – 2015. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration16(5–6), 291–292.
6.Al-Chalabi, A., Hardiman, O., Kiernan, M. C., Chiò, A., Rix-Brooks, B., & van den Berg, L. H. (2016). Amyotrophic lateral sclerosis: Moving towards a new classification system. The Lancet Neurology15(11), 1182–1194.
7.Swinnen, B., & Robberecht, W. (2014). The phenotypic variability of amyotrophic lateral sclerosis. Nature Reviews Neurology10(11), 661–670.
8.Phukan, J., Elamin, M., Bede, P., Jordan, N., Gallagher, L., Byrne, S., … Hardiman, O. (2012). The syndrome of cognitive impairment in amyotrophic lateral sclerosis: A population-based study. Journal of Neurology, Neurosurgery and Psychiatry83(1), 102–108.
9.Ringholz, G. M., Appel, S. H., Bradshaw, M., Cooke, N. A., Mosnik, D. M., & Schulz, P. E. (2005). Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology65(4), 586–590.
10.Barson, F. P., Kinsella, G. J., Ong, B., & Mathers, S. E. (2000). A neuropsychological investigation of dementia in motor neurone disease (MND). Journal of the Neurological Sciences180(1–2), 107–113.
11.Beeldman, E., Raaphorst, J., Twennaar, M. K., De Visser, M., Schmand, B. A., & De Haan, R. J. (2016). The cognitive profile of ALS: A systematic review and meta-analysis update. Journal of Neurology, Neurosurgery and Psychiatry87(6), 611–619.
12.Phukan, J., Pender, N. P., & Hardiman, O. (2007). Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurology6, 994–1003.
13.Gibbons, Z. C., Richardson, A., Neary, D., & Snowden, J. S. (2008). Behaviour in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis9(2), 67–74.
14.Girardi, A., MacPherson, S. E., & Abrahams, S. (2011). Deficits in emotional and social cognition in amyotrophic lateral sclerosis. Neuropsychology25(1), 53–65.
15.Strong, M. J., Grace, G. M., Freedman, M., Lomen-Hoerth, C., Woolley, S., Goldstein, L., … Figlewicz, D. (2009). Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis10(3), 131–146.
16.Canosa, A., Pagani, M., Cistaro, A., Montuschi, A., Iazzolino, B., Fania, P., … Chio, A. (2016). 18F-FDG-PET correlates of cognitive impairment in ALS. Neurology86, 44–49.
17.Lillo, P., Mioshi, E., Burrell, J. R., Kiernan, M. C., Hodges, J. R., & Hornberger, M. (2012). Grey and white matter changes across the amyotrophic lateral sclerosis-frontotemporal dementia continuum. PLoS ONE7(8).
18.Strong, M. J. (2001). Progress in clinical neurosciences: The evidence for ALS as a multisystems disorder of limited phenotypic expression. Canadian Journal of Neurological Sciences28, 283–298.
19.Agosta, F., Valsasina, P., Riva, N., Copetti, M., Messina, M. J., Prelle, A., … Filippi, M. (2012). The cortical signature of amyotrophic lateral sclerosis. PLoS ONE7(8).
20.Agosta, F., Canu, E., Valsasina, P., Riva, N., Prelle, A., Comi, G., & Filippi, M. (2013). Divergent brain network connectivity in amyotrophic lateral sclerosis. Neurobiology of Aging34(2), 419–427.
21.Neumann, M., Sampathu, D., Kwong, L., Truax, A., Micsenyi, M., Chou, T., … Lee, V. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science314(5796), 130–133.
22.DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., … Rademakers, R. (2011). Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron72(2), 245–256.
23.Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J. R., … Traynor, B. J. (2011). A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron72(2), 257–268.
24.Olney, R. K., Murphy, J., Forshew, D., Garwood, E., Miller, B. L., Langmore, S., … Lomen-Hoerth, C. (2005). The effects of executive and behavioral dysfunction on the course of ALS. Neurology65(11), 1774–1777.
25.Elamin, M., Phukan, J., Bede, P., Jordan, N., Byrne, S., Pender, N., & Hardiman, O. (2011). Executive dysfunction is a negative prognostic indicator in patients with ALS without dementia. Neurology76(14), 1263–1269.
26.Mioshi, E., Caga, J., Lillo, P., Hsieh, S., Ramsey, E., Devenney, E., … Kiernan, M. C. (2014). Neuropsychiatric changes precede classic motor symptoms in ALS and do not affect survival. Neurology82(2), 149–154.
27.Lillo, P., Mioshi, E., & Hodges, J. R. (2012). Caregiver burden in amyotrophic lateral sclerosis is more dependent on patients’ behavioral changes than physical disability: A comparative study. BMC Neurology12
28.Wicks, P., & Frost, J. (2008). ALS patients request more information about cognitive symptoms. European Journal of Neurology15(5), 497–500.


Tags: ,