An overview of screening instruments for cognition and behavior in patients with ALS: selecting the appropriate tool for clinical practice

Figures & data

Figure 1 Search strategy used for searching Medline and Embase.

Figure 2 PRISMA flowchart of the literature search strategy.

Figure 3 Included studies dedicated to the different screening instruments, split on cognition and behavior. Some of the cognitive screeners also included a behavioral domain (marked with *), and vice versa (marked with “).

Table 1 Characteristics of cognitive screening instruments used for ALS patients.

Specific for	ACE-R	ALS-BCA	ALS-CBS	ECAS	FAB	MMSE	MoCA	PSSFTS	UCSF-SB	BBI	DAS	FrSBe
	Dementia and MCI	ALS	ALS	ALS	Executive dysfunction	General cognition	Dementia and MCI	ALS(-FTD)	ALS	Executive /language subscale	Executive subscale	Executive subscale
Cognitive domains
Executive	–	+	+	+	+	+	+	+	+^b	+	+	+
Attention	+	–	+	–	–	+	+	+	+^b	–	+	+
Fluency	+	+	+	+	+	–	+	+	+	–	–	–
Language	+	–	–	+	–	+	+	+	–	+	–	–
Memory	+	+^recall	+^WM	+	–	+^recall	+^recall	+	+^b	–	–	+^WM
Social cognition	–	–	–	+	–	–	–	–	–	+	–	–
Visuospatial	+	–	–	+	–	+	+	+	–	–	–	–
Behavioral domain	–	+^a	+	+	–	–	–	+^a	+^a	+^Table 2	+^Table 2	+^Table 2
Adaptability^c	V/W +/–	Ty/W/V +	V/W/SD/E +	V/W/E +	V/W/H/F/T +/–	V/W –	V/W +/–	V/W/B/SD +	+	Table 2	Table 2	Table 2
Participants who completed screener	54–87%	–	–	100%	50-100%	91–100%	60-100%	–	–	Table 2	Table 2	Table 2
Administration time	±15 min	5-10 min	5-10 min	15-45 min	5-10 min	10-15min	10-15 min	15-20 min	40 min	Table 2	Table 2	Table 2
Validation
Sensitivity	–	64%	85-90%	50-100%	89-100%	8-13%	–	–	–	Table 2	Table 2	Table 2
Specificity	–	–	62-87%	80-95%	59-100%	100%	–	–	–
PPV	–	–	69-76%	38-73%	57-100%	100%	–	–	–
NPV	–	–	77-86%	92-100%	89-100%	42-63%	–	–	–
Patients with cognitive deficits	30–45%	53%	46–59%	18–37%	14–55%	0–15%	53%	1–56%	–	–	–	20–46%
Alternative versions	+ A,B,C	–	–	+ A,B,C	–	–	+ 1,2,3	–	–	Table 2	Table 2	Table 2
Available languages^d	17	1	3	23	8	73	±100	1	1	Table 2	Table 2	Table 2
Available cutoff^e	+	+	+	+	+	+	+	+^f	+^g	Table 2	+	Table 2
Cutoff corrected for	–	–	–	Age, education	Age, education	–	Education	–	–	Table 2	Table 2	Table 2
References	(94–96)	(62)	(63,82,97,98)	(64,85,88,99–106,120)	(73,88,90,95,105, 107–113)	(71,94,98,109,110, 112,114–117)	(105,111,117,118)	(68,119)	(69)	(73,125)	(81,121)	(71,73,122–124)

ACE-R: Addenbrooke’s Cognitive Examination – revised; ALS-BCA: ALS-Brief Cognitive Assessment; ALS-CBS: ALS-Cognitive Behavioral Screen; ALS-FTD: amyotrophic lateral sclerosis-frontotemporal dementia; ECAS: Edinburgh Cognitive and Behavioral ALS Screen; FAB: Frontal Assessment Battery; MCI: mild cognitive impairment; MMSE: Mini Mental State Examination; MoCA: Montreal Cognitive Assessment; NPV: Negative Predictive Value; PBA: pseudobulbar affect; PBAC: Philadelphia Brief Assessment of the Cognition; PPV: Positive Predictive Value; PSSFTS: Penn State Screening examination of Frontal and Temporal dysfunction Syndromes; UCSF-SB: UCSF screening battery; WM: working memory; –: not available/unknown; +: available.

^aBehavioural domain is assessed with the use of the Frontal Behavioral Inventory (FBI).

^bCognitive domains are assessed with the use of the ALS-CBS.

^c(B) blinking (E) eye tracker (F/H/T) tapping with feet/hands or clicking with teeth (SD) speech devices (Ty) typing (V) verbal (W) written.

^dSee Appendix for a list of the available languages; not all languages were used before in ALS patients.

^eCutoff scores are often based on other patient groups than ALS.

^f% within deficient range.

^gSeparately for each subtest.

Table 2 Characteristics of behavioral screening instruments used for ALS patients.

Specific for	ALS-FTD-Q	AES	BBI	DAS	FBI	FrSBe	MiND-B	NPI	ALS-CBS	ECAS
	ALS(-FTD)	Acquired brain injury	ALS	Neurode-generative diseases^a	FTD	Frontal behavior	ALS	Dementia	Behavioral subscale	Behavior interview
Behavioral domain^b
Disinhibition	+	–	+	+	+	+	+	+	+	+
Apathy; inertia	+	+	+	+	+	+	+	+	+	+
Sympathy; empathy	+	–	+	+	–	+	–	–	+	+
Perseverations; stereotyped; compulsive/ritualistic behavior	+	–	+	–	+	–	+	–	–	+
Hyperorality; dietary changes	+	–	+	–	+	–	–	+	+	+
Cognitive domain	+^c	–	+	+	–	+	–	–	+^Table 1	+^Table 1
Considers motor-related problems	+	+/−^d	+	+	–	–	+^e	–	–	–
Reporter	Proxy	Self-report/proxy/clinician	Proxy	Self-report/proxy	Proxy	Self-report/proxy	Proxy/clinician	Proxy	Proxy	Proxy
Number of items	25	18	41	24	24	46	9	12	15	10
Administration time	5–10 min	10–20 min	5–10 min	10–15 min	15–30 min	10 min	–	5 min	Table 1	25–50 min
Output scores	composite score	composite score	composite score	3 subscales^f	2 subscales^g	3 subscales^h	3 subscales^i	3 subscales^j	composite score	composite score
Type questions	4-point rating scale	4-point rating scale	4-point rating scale	4-point rating scale	4-point rating scale	6-point rating scale	4-point rating scale	3/4-point rating scale	3-point rating scale	2-point rating scale
Validation
Sensitivity	−^k	–	50–100%	62%	–	–	81–90%	–	83–93%	–
Specificity	–	–	76–96%	82%	–	–	50–75%	–	69–86%	–
PPV	–	–	72.5%	58%	–	–	77.8%	–	25–94%	–
NPV	–	–	91.1%	85%	–	–	72.7%	–	67–97%	–
Patients with (mild) behavioral changes	18–32%	24%	14–47%	24–43%	33–46%	13–56%	39–75%	19–75%	9–34%	14–65%
Available languages^l	9	10	1	4	5	14	1	75	Table 1	Table 1
Available cutoff^m	+	+	+	+	+	+	+	–	+	–
References	(71,90,95,125)	(121)	(73,125)	(81,121)	(68,71,126)	(71,73,122–124)	(77,95)	(109,127,128)	(63,82,97, 98)	(64,85,88, 99–106,120)

AES: Apathy Evaluation Scale; ALS-FTD-Q: Amyotrophic Lateral sclerosis – Frontotemporal Dementia – Questionnaire; BBI: Beaumont Behavioral Inventory; DAS: Dimensional Apathy Scale; FBI: Frontal Behavioral Inventory; FrSBe: Frontal Systems Behavior scale; MiND-B: Motor Neuron Disease Behavior Scale; NPI: Neuropsychiatric Inventory; –: not available/unknown; +: available.

^aWith motor impairments

^bRascovsky criteria (8).

^c3 items on memory, concentration, and orientation in time.

^dMarin’s definition of apathy was modified, adding: "lack of motivation not attributable to diminished level of .., motor dysfunction; …” (129).

^eInstrument to detect non-motor symptoms in ALS.

^fExecutive, emotional, initiation.

^gNegative and positive behavior.

^hApathy, disinhibition, executive dysfunction.

ⁱDisinhibition, apathy, stereotypy.

^jNumber of symptoms, severity of symptoms, caregiver distress.

^kConstruct validity was assessed (71,90).

^lSee Appendix for a list of the available languages; not all languages were used before in patients with ALS.

^mCutoff scores are often based on different patient groups.

Table

Cognitive screeners
ACE-R	Czech; English; Farsi; Flemish; French; German; Greek; Hindi; Italian; Japanese; Mandarin; Polish; Portuguese; Spanish; Swedish; Telugu; and Turkish
ALS-BCA	English
ALS-CBS	English; Portuguese; and Spanish
ECAS	American; Belgium; Chinese; Croatian; Czech; Dutch; English; French; German; Swiss-German; Greek; Hebrew; Italian; Japanese; Norwegian; Polish; Portuguese; Russian; Slovak; Slovenian; Spanish; Swedish; and Welsh
FAB	Dutch; English; French; German; Italian; Persian; Portuguese (Brazilian); and Spanish
MMSE	Afrikaans; Albanian; Arabic; Argentinean Spanish; Armenian; Austrian German; Basque; Belgian Dutch; Belgian French; Bengali; Bosnian; Bulgarian; Catalan; Chilean Spanish; Chinese (Hong Kong/Malaysia/ Singapore/Taiwan); Croatian; Czech; Danish; Dutch; English; Estonian; Farsi; Filipino; Finnish; French (Canadian); Georgian; German; Greek; Gujarati; Hebrew; Hindi; Hungarian; Icelandic; Indian English; Israeli English; Italian; Japanese; Kannada; Korean; Latvian; Lithuanian; Macedonian; Malay; Malayalam; Marathi; Norwegian; Polish; Portuguese (Brazilian); Punjabi; Romanian; Russian; Serbian; Slovak; Slovene; Sotho; South African English; Spanish (USA); Swedish; Tamil; Telugu; Thai; Turkish; Ukrainian; Urdu; Vietnamese; and Zulu
MoCA^b	English (Singapore); Afrikaans; Arabic; Bengali; Bulgarian; Chinese (Beijing/ Cantonese/Changsha/Hong Kong/Maderian/Mandarin/Minnan/Singapore); Creole (Cape Verdean); Croatian; Czech; Danish; Dutch; Estonian; Filipino; Finnish; French; Georgian; German; Greek; Gujarati; Hebrew; Hindi; Hungarian; Italian; Japanese; Kannada; Korean; Korean (K2-Chuncheon); Latvian; Lithuanian; Malay (Bahasa-Malaysia); Malay (Singapore); Malayalam; Marathi; Myanmar; Norwegian; Persian; Polish; Portuguese; Portuguese (Brazilian); Punjabi; Romanian; Russian; Serbian; Sinhalese; Slovak; Slovenian; Spanish; Swahili; Swedish; Taiwan; Tamil; Telugu; Thai; Turkish; Ukrainian; Urdu; Uyghur; Vietnamese; and Welsh
PSSFTS	English
UCSF-SB	English
Behavioral screeners
ALS-FTD-Q	Danish; Dutch; English; French; German; Italian; Japanese; Serbian; and Spanish.
AES	Arabic; Dutch; English; Italian; Japanese; Portuguese; Russian; Spanish; Swedish; and Taiwanese
BBI	English
DAS	English; French; Greek; and Italian
FBI	English; French; Italian; Korean; and Portuguese (Brazilian)
FrSBe	Afrikaans; Chinese; Czech; Dutch; French; German; Icelandic; Italian; Japanese; Polish; Romanian; Spanish; Swedish; and Portuguese (Brazilian)
MiND-B	English
NPI	English (USA); Afrikaans; Bengali; Bulgarian; Cantonese (China/Hong-Kong); Chinese (Hong-Kong(Cantonese or Mandarin)/Singapore/Taiwan); Croatian; Czech; Danish; Dutch (Belgium); English (Australia/Canada/Hong-Kong/India/Israel/Malaysia/New Zealand/ Philippines/Singapore/South Africa/UK/USA); Estonian; Finnish; French (Belgium/Canada); German; German (Switzerland); Greek; Gujarati; Hebrew; Hindi; Hungarian; Italian; Japanese; Kannada; Korean; Malay; Malayalam; Mandarin (China/Malaysia/Singapore); Marathi; Norwegian; Polish; Portuguese (Brazilian); Punjabi Romanian; Russian (Estonia/ Israel/Ukraine); Serbian; Slovak; Slovenian; Spanish (Argentina/Chile/Mexico/Peru/USA); Swedish; Tagalog; Tamil (Malaysia); Telugu; Turkish; Ukrainian; and Urdu

^aThere is no certainty of mentioning all translations, since there is often no consensus on the number of available translations.

^bMoCA test’s official website states that the test is available in nearly 100 languages. 67 languages are registered in the current overview based on their website.

Hu WT, Shelnutt M, Wilson A, Yarab N, Kelly C, Grossman M, et al. Behavior matters-cognitive predictors of survival in amyotrophic lateral sclerosis. PLoS One. 2013;8: e57584.

 PubMed Web of Science ®Google Scholar

Woolley SC, York MK, Moore DH, Strutt AM, Murphy J, Schulz PE, et al. Detecting frontotemporal dysfunction in ALS: utility of the ALS Cognitive Behavioral Screen (ALS-CBSTM). Amyotroph Lateral Scler. 2010;11:303–11.

 PubMed Web of Science ®Google Scholar

Turon-Sans J, Gascon-Bayarri J, Reñé R, Rico I, Paipa A, Povedano M, et al. Cognitive impairment in ALS patients and validation of the Spanish version of the ALS-CBS test. Amyotroph Lateral Scler Front Degener. 2016;17:221–7.

 PubMed Web of Science ®Google Scholar

Branco LMT, Zanao T, Rezende TD, Casseb RF, Balthazar MF, Woolley SC, et al. Transcultural validation of the ALS-CBS Cognitive Section for the Brazilian population. Amyotroph Lateral Scler Front Degener. 2017;18:60–7.

 PubMed Web of Science ®Google Scholar

Rabkin J, Goetz R, Murphy J, Factor-Litvak P, Mitsumoto H. Cognitive impairment, behavioral impairment, depression, and wish to die in an ALS cohort. Neurology 2016;87:1320–8.

 PubMed Web of Science ®Google Scholar

Abrahams S, Newton J, Niven E, Foley J, Bak TH. Screening for cognition and behaviour changes in ALS. Amyotroph Lateral Scler Front Degener. 2014;15:9–14.

 PubMed Web of Science ®Google Scholar

Crockford C, Newton J, Lonergan K, Chiwera T, Booth T, Chandran S, et al. ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS. Neurology. 2018;91:E1370–80.

 PubMed Web of Science ®Google Scholar

Burkhardt C, Neuwirth C, Weber M. Longitudinal assessment of the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS): lack of practice effect in ALS patients?. Amyotroph Lateral Scler Front Degener. 2017;18:202–9.

 PubMed Web of Science ®Google Scholar

Pinto-grau M, Burke T, Lonergan K, Mchugh C, Mays I, Madden C, et al. Screening for cognitive dysfunction in ALS: validation of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) using age and education adjusted normative data. Amyotroph Lateral Scler Front Degener. 2017;18:99–106.

 PubMed Web of Science ®Google Scholar

Elamin M, Pinto-grau M, Burke TOM, Bede P, Rooney J, Sullivan MO, et al. Identifying behavioural changes in ALS: validation of the Beaumont Behavioural Inventory (BBI). Amyotroph Lateral Scler Front Degener. 2017;18:68–73.

 PubMed Web of Science ®Google Scholar

Watanabe Y, Beeldman E, Raaphorst J, Izumi Y, Yoshino H, Masuda M, et al. Japanese version of the ALS-FTD-Questionnaire (ALS-FTD-Q-J). J Neurol Sci. 2016;367:51–5.

 PubMed Web of Science ®Google Scholar

Xu Z, Alruwaili ARS, Henderson RD, McCombe PA. Screening for cognitive and behavioural impairment in amyotrophic lateral sclerosis: frequency of abnormality and effect on survival. J Neurol Sci. 2017;376:16–23.

 PubMed Web of Science ®Google Scholar

Poletti B, Solca F, Carelli L, Faini A, Lafronza A, Monti A, et al. Cognitive-behavioral longitudinal assessment in ALS: the Italian Edinburgh Cognitive and Behavioral ALS screen (ECAS). Amyotroph Lateral Scler Front Degener. 2018;19:387–95.

 PubMed Web of Science ®Google Scholar

Raaphorst J, Beeldman E, Schmand BA, Berkhout J, Linssen W, Berg Van Den LH, et al. The ALS-FTD-Q: a new screening tool for behavioral disturbances in ALS. Neurology 2012; 79:1377–83.

 PubMed Web of Science ®Google Scholar

Wei Q, Chen X, Zheng Z, Huang R, Guo X, Cao B, et al. Screening for cognitive impairment in a Chinese ALS population. Amyotroph Lateral Scler Front Degener. 2015;16:40–5.

 PubMed Web of Science ®Google Scholar

Ahn S, Kim S-H, Kim J, Kim S-M, Kim SH, Sung J-J, et al. Frontal assessment battery to evaluate frontal lobe dysfunction in ALS patients. Can J Neurol Sci. 2011;38:242–6.

 PubMed Web of Science ®Google Scholar

Floris G, Borghero G, Chi A, Secchi L, Cannas A, Sardu C, et al. Cognitive screening in patients with amyotrophic lateral sclerosis in early stages. Amyotroph Lateral Scler. 2012;13:95–101.

 PubMed Web of Science ®Google Scholar

Oskarsson B, Quan D, Rollins YD, Neville HE, Ringel SP, Arciniegas DB. Using the Frontal Assessment Battery to identify executive function impairments in amyotrophic lateral sclerosis: a preliminary experience. Amyotroph Lateral Scler. 2010;11:244–7.

 PubMed Web of Science ®Google Scholar

Osborne RA, Sekhon R, Johnston W, Kalra S. Screening for frontal lobe and general cognitive impairment in patients with amyotrophic lateral sclerosis. J Neurol Sci. 2014;336:191–6.

 PubMed Web of Science ®Google Scholar

Zhu W, Fu X, Cui F, Yang F, Ren Y, Zhang X, et al. ALFF value in right parahippocampal gyrus acts as a potential marker monitoring amyotrophic lateral sclerosis progression: a neuropsychological, voxel-based morphometry, and resting-state functional MRI study. J Mol Neurosci. 2015;57:106–13.

 PubMed Web of Science ®Google Scholar

Tremolizzo L, Pellegrini A, Conti E, Arosio A, Gerardi F, Lunetta C, et al. BDNF serum levels with respect to multidimensional assessment in amyotrophic lateral sclerosis. Neurodegener Dis. 2016;16:192–8.

 PubMed Web of Science ®Google Scholar

Flaherty-Craig C, Brothers A, Dearman B, Eslinger P, Simmons Z. Penn State screen exam for the detection of frontal and temporal dysfunction syndromes: application to ALS. Amyotroph Lateral Scler. 2009;10:107–12.

 PubMed Web of Science ®Google Scholar

Flaherty-Craig C, Brothers A, McFalls A, Yang C, Simmons Z. VALUES: a national multicenter study of regional and gender differences in frontotemporal disease in amyotrophic lateral sclerosis. Neurodegener Dis Manag. 2012;2:325–36.

 Google Scholar

Murphy J, Ahmed F, Lomen-Hoerth C, Murphy J, Ahmed F, Lomen-Hoerth C. The UCSF screening exam effectively screens cognitive and behavioral impairment in patients with ALS. Amyotroph Lateral Scler Front Degener. 2015;16:24–30.

 PubMed Web of Science ®Google Scholar

Pinto-Grau M, Costello E, O’Connor S, Elamin M, Burke T, Heverin M, et al. Assessing behavioural changes in ALS: cross-validation of ALS-specific measures. J Neurol. 2017;264:1397–401.

 PubMed Web of Science ®Google Scholar

Santangelo G, Siciliano M, Trojano L, Femiano C, Monsurrò R, Tedeschi G, et al. Apathy in amyotrophic lateral sclerosis: insights from Dimensional Apathy Scale. Amyotroph Lateral Scler Front Degener. 2017; 18:434–42.

 PubMed Web of Science ®Google Scholar

Radakovic R, Stephenson L, Colville S, Swingler R, Chandran S, Abrahams S. Multidimensional apathy in ALS: validation of the Dimensional Apathy Scale. J Neurol Neurosurg Psychiatry. 2016;87:663–9.

 PubMed Web of Science ®Google Scholar

Wei Q, Chen XP, Zheng ZZ, Huang R, Guo XY, Cao B, et al. Frontal lobe function and behavioral changes in amyotrophic lateral sclerosis: a study from Southwest China. J Neurol. 2014;261:2393–400.

 PubMed Web of Science ®Google Scholar

Mioshi E, Hsieh S, Caga J, Ramsey E, Chen K, Lillo P, et al. A novel tool to detect behavioural symptoms in ALS. Amyotroph Lateral Scler Front Degener. 2014;15:298–304.

 PubMed Web of Science ®Google Scholar

Oh SI, Park A, Kim H, Oh K, Choi H, Kwon M, et al. Spectrum of cognitive impairment in Korean ALS patients without known genetic mutations. PLoS One. 2014;9:e87163.

 PubMed Web of Science ®Google Scholar

Wei Q, Chen X, Cao B, Ou R, Zhao B, Wu Y, et al. Associations between neuropsychiatric symptoms and cognition in Chinese patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Front Degener. 2016;17:358–65.

 PubMed Web of Science ®Google Scholar

Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134:2456–77.

 PubMed Web of Science ®Google Scholar

Glenn, M. B., Burke, D. T., O'Neil-Pirozzi, T., Goldstein, R., Jacob, L., & Kettell, J. (2002). Cutoff score on the apathy evaluation scale in subjects with traumatic brain injury. Brain Injury, 16(6), 509–516. https://doi.org/10.1080/02699050110119132

 Google Scholar