Italian reference values and brain correlates of verbal fluency index – vs standard verbal fluency test – to assess executive dysfunction in ALS

Figures & data

Table 1 Sociodemographic and clinical features of the sample.

	HC	ALS	p Values
N	180	157
Age [years]	63.44 ± 10.49 (29–85)	59.71 ± 10.68 (24–83)	0.001
Sex, women	114 (63.33%)	73 (46.50%)	0.001
Education [years]	12.88 ± 4.08 (5–23)	11.14 ± 4.32 (4–28)	<0.001
ALSFRS-R, 0–48	–	38.00 ± 6.11 (22–48)	–
Disease duration [months]	–	20.96 ± 17.68 (4–94)	–
Disease progression rate	–	0.70 ± 0.63 (0 − 2.67)	–

Notes: Values denote mean ± standard deviation (percentages or minimum-maximum values). p Values refer to Mann–Whitney’s test and Fisher’s exact test for continuous and categorical variables, respectively. Abbreviations: ALS: Amyotrophic Lateral Sclerosis; ALSFRS-R: ALS Functional Rating Scale revised; HC: Healthy Controls. Disease Progression Rate has been obtained as following: (48–ALSFRS-R score)/time between symptom onset and first visit.

Table 2 Neuropsychological assessment of the sample.

	HC	ALS	p Values
N	180	157
Global cognition
MMSE	29.32 ± 0.87 (27–30)	28.37 ± 1.84 (20–30)	<0.001
ECAS language	–	24.21 ± 4.23 (12–28)	–
ECAS fluency	–	16.76 ± 6.62 (0–22)	–
ECAS executive functions	–	35.91 ± 7.47 (10–46)	–
ECAS ALS-specific functions	–	77.00 ± 16.31 (38–96)	–
ECAS memory	–	16.26 ± 4.94 (1–23)	–
ECAS visuospatial	–	11.44 ± 1.19 (6–12)	–
ECAS ALS nonspecific functions	–	27.71 ± 5.14 (12–35)	–
ECAS total score	–	103.30 ± 20.82 (45–129)	–
Memory
RAVLT, delayed recall	9.74 ± 2.89 (3–15)	8.62 ± 3.36 (0–15)	0.01
Digit span forward	6.01 ± 0.98 (4–9)	5.47 ± 1.08 (3–8)	<0.001
Spatial span	5.18 ± 1.08 (2–7)	4.77 ± 0.82 (3–6)	0.11
Executive functions
WCST, perseverations	8.82 ± 5.46 (4–25)	21.97 ± 22.90 (3–101)	0.02
MCST, perseverations	4.39 ± 5.28 (0–39)	4.75 ± 5.90 (0–25)	0.61
Digit span, backward	4.69 ± 1.11 (2–8)	4.12 ± 1.20 (0–6)	0.001
Raven’s matrices	31.29 ± 3.59 (17–36)	28.74 ± 5.31 (14–36)	<0.001
Cognitive estimation task	–	14.32 ± 3.94 (6–26)	–
Stroop test, errors	–	4.02 ± 9.57 (0–50)	–
Weigl’s sorting test	–	11.53 ± 3.10 (1–15)	–
Trail making test B–A	64.92 ± 35.95 (0–265.12)	–	–
Attentive matrices	52.29 ± 6.24 (27–60)	–	–
Fluency
Phonemic verbal fluency test (VFT)	39.06 ± 10.64 (12–81)	30.92 ± 12.28 (4–59)	<0.001
Phonemic fluency index (Vfi)	4.68 ± 1.97 (1.7–17.82)	7.61 ± 7.70 (1.81–68.79)	<0.001
Semantic fluency test	47.71 ± 10.12 (25–72)	39.01 ± 11.06 (4–66)	<0.001
Semantic fluency index	3.96 ± 1.72 (0–12.56)	5.41 ± 4.92 (2–44.49)	<0.001
Language
BADA, nouns	29.59 ± 1.12 (25–30)	28.73 ± 2.16 (13–30)	0.002
BADA, actions	27.34 ± 1.40 (21–28)	26.39 ± 2.51 (17–30)	0.03
Token test	33.83 ± 1.99 (27–36)	–	–
Visuospatial abilities
Rey figure, recall	16.16 ± 5.90 (4.5–29)	–	–
Benson figure, recall	11.25 ± 2.97 (4–17)	–	–
Social cognition
SET global score	–	14.85 ± 3.17 (7–18)	–
SET intention attribution	–	4.88 ± 1.32 (2–6)	–
SET causal inference	–	5.06 ± 1.03 (2–6)	–
SET emotion attribution	–	4.85 ± 1.37 (1–6)	–
Psychopathology
HDRS	–	6.23 ± 4.91 (0–24)	–
BDI	6.73 ± 5.07 (0–29)	9.59 ± 7.84 (0–37)	0.03
ALS-FTD-Q	–	11.79 ± 12.57 (0–52)	–
NPI	–	5.31 ± 6.38 (0–28)	–

Notes: Values denote mean ± standard deviation (minimum–maximum values). p Values refer to Mann–Whitney’s test. Abbreviations: ALS: Amyotrophic Lateral Sclerosis; ALS-FTD-Q: ALS-Frontotemporal lobar degeneration Questionnaire; BADA: Italian battery for the assessment of aphasic disorders; BDI: Beck Depression Inventory; ECAS: Edinburgh Cognitive and Behavioral ALS Screen; HC : Healthy Controls; HDRS: Hamilton Depression Rating Scale; MCST: Modified Card Sorting Test; MMSE: Mini Mental State Examination; NPI: Neuropsychiatric Inventory; RAVLT: Rey Auditory Verbal Learning Test; SET: Story-Based Empathy Task; WCST: Wisconsin Card Sorting Test.

Table 3 Reference data and cutoffs for the verbal fluency index (Vfi) in each subgroup of healthy controls.

	Males				Females
Education (years)	< =13		>13		< =13		>13
No. of subjects	(N = 40)		(N = 27)		(N = 76)		(N = 37)
Spoken Vfi	Mean ± SD (median; range IQR)	Cutoff^a	Mean ± SD (median; range IQR)	Cutoff^a	Mean ± SD (median; range IQR)	Cutoff^a	Mean ± SD (median; range IQR)	Cutoff^a
	5.26 ± 1.84 (5.06; 1.95)	16.05	4.37 ± 1.49 (3.90; 1.42)	12.41	4.92 ± 2.31 (4.33; 2.07)	16.89	3.79 ± 1.18 (3.74; 1.50)	6.88

^aThe cutoff refers to the upper limit of the 95th percentile confidence interval (see distributions of healthy control performances in the Supplementary Figure 1).

Figure 1 Application of VFT and Vfi cutoffs. Graphs display the percentages of ALS patients with an impaired and normal performance applying VFT and Vfi cutoffs. p Value refers to Fisher’s exact test.

Figure 2 Significant relationships between patients’ verbal fluency test and verbal fluency index performances with their white matter tract integrity. Abbreviations: CC: corpus callosum; CC-SMA: callosal fibers linking the supplementary motor area; CST: corticospinal tract; L: left; R: right; SLF: superior longitudinal fasciculus.

Table 4 Significant relationships between patients’ verbal fluency test and verbal fluency index performances and their white matter tract integrity.

	Verbal fluency test (VFT)	Verbal fluency index (Vfi)
CC, MD	C: −40.11; p = 0.04
CC, radD	C: −42.68; p = 0.01
CC-SMA, FA	C: 97.27; p = 0.002
CC-SMA, MD	C: −68.30; p = 0.01	C: 24.46; p = 0.01
CC-SMA, radD	C: −64.35; p = 0.002	C: 18.42; p = 0.02
SLF R, FA	C: 71.33; p = 0.02
SLF R, MD	C: −48.88; p < 0.001
SLF R, radD	C: −49.18; p < 0.001
SLF L, radD	C: −59.76; p = 0.02
CST R, MD	C: −23.96; p < 0.001
CST R, axD	C: −22.18; p = 0.04

Notes: Significant results of adjusted quantile regression between verbal fluency test and verbal fluency index scores and white matter tract integrity, accounting for age at MRI, sex, and education. Abbreviations: axD: axial diffusivity; C: regression coefficient; CC: corpus callosum; FA: fractional anisotropy; L: left; MD: mean diffusivity; R: right; radD: radial diffusivity; SLF: superior longitudinal fasciculus; SMA: supplementary motor area.

Data availability statement

The dataset used during the study will be made available by the corresponding author upon request to qualified researchers (i.e. affiliated with a university or research institution/hospital).