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

<i>Objectives:</i> In amyotrophic lateral sclerosis (ALS), verbal fluency index (V<i>fi</i>) is used to investigate fluency accounting for motor impairment. This study has three aims: (1) to provide V<i>fi</i> reference values from a cohort of Italian healthy subjects; (2) to assess the ability of V<i>fi</i> reference values (<i>vs</i> standard verbal fluency test [VFT]) in distinguishing ALS patients with and without executive dysfunction; and (3) to investigate the association between V<i>fi</i> and brain structural features of ALS patients. <i>Methods:</i> We included 180 healthy subjects and 157 ALS patients who underwent neuropsychological assessment, including VFT and V<i>fi</i>, and brain MRI. Healthy subjects were split into four subgroups according to sex and education. For each subgroup, we defined the 95th percentile of V<i>fi</i> as the cutoff. In ALS, the distributions of "abnormal" cases based on V<i>fi</i> and standard VFT cutoffs were compared using Fisher's exact test. Using quantile regressions in patients, we assessed the association between V<i>fi</i> and VFT scores, separately, with gray matter volumes and white matter (WM) tract integrity. <i>Results:</i> Applying V<i>fi</i> and VFT cutoffs, 9 and 13% of ALS cases, respectively, had abnormal scores (<i>p</i> < 0.001). In ALS, while higher V<i>fi</i> scores were associated with WM changes of callosal fibers linking supplementary motor area, lower VFT performances related to corticospinal tract alterations. <i>Discussion:</i> We provided Italian reference values for the spoken V<i>fi</i>. Compared to VFT, V<i>fi</i>s are critical to disentangle motor and cognitive deficits in ALS. In patients, abnormal V<i>fi</i>s were associated with damage to WM tracts specifically involved in ideational information processing.