29 Jan 2016

The majority of people with amyotrophic lateral sclerosis (ALS) also manifest signs of cognitive or behavioral impairment. Indeed, in about one-fifth of these patients, those symptoms are severe enough that they might have frontotemporal dementia, according to a large, multicenter analysis. Writing in the January 27 Neurology online, the study authors distinguished between symptoms of cognitive impairment, such as trouble juggling mental tasks, and behavioral impairment, such as apathy, among 274 people with ALS. They found that behavioral changes, in particular, were associated with poorer ability to move, breathe, speak, and swallow.

“This study tells us that behavior change in ALS patients is important to identify clinically important risk factors,” said first author Jennifer Murphy of the University of California, San Francisco.

While an ALS diagnosis requires only motor symptoms, prior studies have indicated that 8 to 15 percent of people with the condition also suffer from dementia, and that many more have milder problems with thinking or behavior (see Related Papers, below). Several previous studies were small, however, making it difficult to determine the prevalence of ALS-related dementia, or separate cognitive from behavioral symptoms, with any precision. Murphy and colleagues analyzed these symptoms in a larger group who participated in the Multicenter Cohort Study of Oxidative Stress (ALS-COSMOS). In this epidemiological study, 355 people newly diagnosed with sporadic ALS offered up blood, urine, and skin samples as well as data on their lifestyle (Mitsumoto et al., 2014). Two hundred and seventy-four of the volunteers also participated in the cognitive study, undergoing their first evaluations within 18 months of their initial symptoms. While COSMOS is a longitudinal study, the authors only report baseline data in this paper.

The main measure Murphy and collaborators used was the two-part ALS Cognitive Behavioral Screen (ALS-CBS) (Woolley et al., 2010). Its cognitive questionnaire, given verbally, focuses on executive function defects often associated with ALS. For example, one item asks the test-taker to alternate between letters and numbers in a pattern: 1A, 2B, 3C, and so on. The authors considered a score of zero-10 possible FTD, 11-16 cognitive impairment, and 17-20 normal. In addition, the authors gave caregivers a written behavioral questionnaire, with questions such as, “Has the patient shown less interest in topics or events that used to be important?” In this case, scores up to 32 were considered possible FTD, 33-36 behavioral impairment, and 37-42 unaffected.

These were only screening tools, not detailed neuropsychiatric evaluations, Murphy said. These screens cannot diagnose dementia but merely indicate who might need further testing. However, the use of a short screen made it possible to evaluate many people at clinics across the country, said co-author Hiroshi Mitsumoto of Columbia University in New York, who leads the COSMOS program.

In terms of cognition, 39 percent of participants were unaffected, 54 percent mildly impaired, and nearly 7 percent scored in the possible dementia range. On the behavior questionnaire, 69 percent were unaffected, 14 percent were impaired, and nearly 17 percent scored as having possible FTD. Common behavioral changes included irritability, confusion, and diminished empathy. Since the study only recruited people diagnosed beforehand with ALS—not those already considered to have combined ALS-FTD—the true rates of dual diagnoses may be higher, suggested John Hodges of the University of New South Wales in Sydney, who did not participate in the study.

The authors examined how these scores correlated with other clinical features, and found that behavior lined up with several measures. People with behavioral problems were likelier to experience classical ALS symptoms in the face and mouth—the “bulbar” area controlled by the brainstem—such as difficulty speaking or swallowing. They were also likelier than others to suffer pseudobulbar affect, the inappropriate laughing or crying spells that can afflict people with ALS, also due to degeneration in the brainstem. In addition, people with behavioral problems scored lower on the ALS Functional Rating Scale, which measures basic motor abilities such as speaking and walking. The worse the behavioral symptoms, the less air volume a person could expel, indicating atrophy of the muscles involved in breathing.

Behavioral problems often accompanied cognitive difficulties, but not always. One hundred and three study volunteers had some level of cognitive difficulty with no behavioral problems, and 23 demonstrated behavioral symptoms but normal cognition. Hodges found the disconnect intriguing. In people with FTD, he said, behavioral alterations predominate but cognition is typically affected too.

Murphy told Alzforum that she cannot yet explain why some people have cognitive and others behavioral problems. She and Hodges both speculated that the answer may lie in which part of the neuroanatomy degenerates. Hodges pointed out that the brain’s motor homunculus lies such that the neurons controlling the face are right next to the orbital and lower parts of the frontal lobe, while the homunculus’ arms and legs connect with lateral parts of the lobe. Depending on which body parts are affected, the disease could spread from the relevant motor neurons to the closest parts of the brain, leading to differing symptoms depending on location, he theorized. Murphy speculated that the brainstem and pons, in the lower back of the brain, might be related to the behavioral symptoms, whereas the cognitive changes result from degeneration of the frontal lobe.

The ALS-COSMOS study collected some tissue samples that might reveal biomarkers associated with cognitive or behavioral scores, but has not yet analyzed them for such correlations, Mitsumoto said.

The current study confirms the rates of dementia symptoms in ALS, and the association between behavioral and bulbar symptoms, seen in some previous studies (reviewed in Achi and Rudnicki, 2012). It shows that it is import for motor neuron disease clinics to also evaluate cognitive and behavioral function, Murphy said. For example, if a person has behavioral symptoms, their physician might check more carefully for signs of pseudobulbar affect, which is treatable (Cruz et al., 2013). Researchers recently came up with treatments for other bulbar symptoms, as well (see Dec 2015 conference news).

Hodges added that caregivers of people with both ALS and behavioral symptoms may require extra support. Plus, he said, clinicians need to know how clearly their patients are thinking so they do not expect them to understand concepts or procedures, or make decisions that they are not equipped to make. A dual ALS-FTD diagnosis also means a poorer prognosis (Elamin et al., 2013).

Dementia symptoms should also be evaluated in clinical trials, Murphy said. For one, neurodegeneration in the brain might affect response to a treatment. For another, people with FTD-like impairments may not take all their medicine as directed. She and others had found previously that people with ALS-FTD are likelier to skip their meds than people with ALS only, and they suggested this might explain why people with ALS-FTD decline faster (Olney et al., 2005).

Hodges wondered if people who had no cognitive or behavioral symptoms at baseline would develop them later. Murphy expects to have the answer in a year or so, as the authors are currently evaluating 12-month follow-up data from COSMOS.

Mitsumoto and colleagues at Columbia have developed a cognitive questionnaire they can administer over the telephone. This would enable larger epidemiologic studies, he said, since scientists could reach people who cannot come to an ALS center for face-to-face evaluation. The authors also suggested that tools like the ALS-CBS, designed for people with movement difficulties, might be useful to evaluate cognitive problems in people with other movement disorders such as Parkinson’s or multiple sclerosis.—Amber Dance

Comments

- Laura Goldstein
  Institute of Psychiatry, Psychology and Neurosciencei
- Posted: 29 Jan 2016
The COSMOS study definitely adds to the understanding of the likely prevalence of cognitive and behavioural involvement in ALS. It has been undertaken by a number of the key professionals in this field and highlights the importance of screening for impairment in patients at an early stage. There are a number of screening batteries designed for this purpose but it is really helpful to have data on the use of the ALS CBS-cog, ALS CBS-behaviour subscale and other measures in such a large sample. The authors are to be congratulated on their study.

View all comments by Laura Goldstein

- Elena Ratti
  Massachusetts General Hospital
- Posted: 16 Feb 2016
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily affecting the motor neurons and leading to progressive muscular weakness and ultimately to death within approximately three to five years from symptom onset. ALS was long believed to spare cognition and behavior; however, based on recent clinical studies, it has been acknowledged that a large proportion of patients suffering from ALS can also experience variable degrees of cognitive impairment and behavioral changes. These manifest particularly as executive dysfunction, apathy, disinhibition and social cognition deficits. In addition, 5 to 15 percent of ALS patients meet the diagnostic criteria for frontotemporal dementia (FTD), a common cause of pre-senile dementia, characterized by behavioral and/or language disturbances. This clinical continuum between ALS and FTD is further supported by common pathology, in the form of accumulation of TDP-43 protein, and by common genetics, such as mutations in the C9orf72 gene.

This compelling association between two neurodegenerative diseases presenting with very different clinical manifestations that deeply affect patients and their caregivers poses the challenge of appropriately identifying, evaluating, managing, and monitoring the overlapping symptoms in the clinical as well as in the research settings.

In this context, the study presented by Dr. Murphy on behalf of the ALS COSMOS study group, focusing on evaluation of cognitive-behavioral impairment in a large cohort of people with ALS, represents an important contribution to the field.

This study utilizes a combination of a selection of previously validated measures of cognition, behavior, and ALS-related symptoms to further characterize how motor, cognitive, and behavioral deficits are intertwined in early ALS (within 18 months from symptom onset).

While the cognitive and behavioral measures utilized are screening rather than diagnostic tools, they have the advantage of not only being easy and fast to administer but they are also specific for ALS. In fact, they have been developed and/or adapted for people with motor neuron disease: They are based on known ALS-related cognitive/behavioral profiles and account for the possible motor deficits, hence their relevance in ALS clinical and research practices, and the importance of screening cognitive/behavioral disturbances typical of motor neuron disease. Along these lines, when assessing C9orf72 mutation carriers, it would be important to also evaluate for delusions and psychotic symptoms that are often present in this population.

The study confirms the remarkable frequency and clinical relevance of cognitive/behavioral symptoms in ALS and it also highlights the significant impact of behavioral changes on functional status that can also greatly affect caregivers’ burden.

The remarkable value of this research resides in the large number of the study participants (n=274) and in the demonstration that, with appropriate training, the implementation of these cognitive/behavioral screening tools is not only possible but valid across different ALS centers on a large scale. This supports the concept that these instruments can be efficiently utilized not only in clinical practice, but also in clinical research and therapeutics development.

The confirmation of the significant overlap between motor and cognitive/behavioral deficits in a large ALS cohort further supports the need to integrate the evaluation of cognitive/behavioral symptoms with motor measures in routine ALS clinical assessments/medical practice as well as in ALS research. To this purpose, a number of screening instruments have been developed.

Furthermore, building on the recent knowledge, the detailed characterization of the pattern and relationships of the cognitive and behavioral changes occurring in ALS described in the study offers invaluable information for effective education of patients and caregivers.

Potential next steps may include studies evaluating the performance of different measures of cognitive/behavioral changes in a large cohort of people with ALS followed over time. Longitudinal studies can provide important information regarding progression of cognitive/behavioral symptoms in ALS and allow more accurate prognostication and inform the potential development of novel clinical endpoints.

View all comments by Elena Ratti

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References

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Mitsumoto H, Factor-Litvak P, Andrews H, Goetz RR, Andrews L, Rabkin JG, McElhiney M, Nieves J, Santella RM, Murphy J, Hupf J, Singleton J, Merle D, Kilty M, Heitzman D, Bedlack RS, Miller RG, Katz JS, Forshew D, Barohn RJ, Sorenson EJ, Oskarsson B, Fernandes Filho JA, Kasarskis EJ, Lomen-Hoerth C, Mozaffar T, Rollins YD, Nations SP, Swenson AJ, Shefner JM, Andrews JA, Koczon-Jaremko BA, ALS COSMOS Study Group. ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): study methodology, recruitment, and baseline demographic and disease characteristics. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Jun;15(3-4):192-203. Epub 2014 Feb 24 PubMed.
Woolley SC, York MK, Moore DH, Strutt AM, Murphy J, Schulz PE, Katz JS. Detecting frontotemporal dysfunction in ALS: utility of the ALS Cognitive Behavioral Screen (ALS-CBS). Amyotroph Lateral Scler. 2010 May 3;11(3):303-11. PubMed.
Achi EY, Rudnicki SA. ALS and Frontotemporal Dysfunction: A Review. Neurol Res Int. 2012;2012:806306. Epub 2012 Aug 7 PubMed.
Cruz MP. Nuedexta for the treatment of pseudobulbar affect: a condition of involuntary crying or laughing. P T. 2013 Jun;38(6):325-8. PubMed.
Elamin M, Bede P, Byrne S, Jordan N, Gallagher L, Wynne B, O'Brien C, Phukan J, Lynch C, Pender N, Hardiman O. Cognitive changes predict functional decline in ALS: a population-based longitudinal study. Neurology. 2013 Apr 23;80(17):1590-7. Epub 2013 Apr 3 PubMed.
Olney RK, Murphy J, Forshew D, Garwood E, Miller BL, Langmore S, Kohn MA, Lomen-Hoerth C. The effects of executive and behavioral dysfunction on the course of ALS. Neurology. 2005 Dec 13;65(11):1774-7. PubMed.

Confirmed: ALS Attacks Cognition and Behavior

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