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

Abstract

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

Keywords:

• Amyotrophic lateral sclerosis
• cognitive classification
• motor neuron disease
• normative data
• verbal fluency index

Declaration of interest

V. Castelnovo, P.M.V. Rancoita, M. Leocadi, A. Lamanuzzi, E.G. Spinelli, S. Basaia, N. Riva, B. Poletti, F. Solca, S. Abrahams report no conflict of interest. E. Canu has received research supports from the Italian Ministry of Health. F. Verde is review editor for Frontiers in Aging Neuroscience. N. Ticozzi received compensation from consulting services from Amylyx Pharmaceuticals and Zambon Biotech SA and lecture fees from Italfarmaco. He received research funding from the Italian Ministry of Health and AriSLA. He is associate editor for Frontiers in Aging Neuroscience. V. Silani received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, and Zambon; and receives research supports from the Italian Ministry of Health (Grant RF-2013-02355764), Fondazione Regione per la Ricerca Biomedica Regione Lombardia (Project nr.2015-0023), and E-RARE JTC 2018 (Project Repetomics). M. Filippi is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Alexion, Almirall, Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen, Merck, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). F. Agosta is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Biogen Idec, Roche and Zambon; and receives or has received research supports from the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), the European Research Council and the Foundation Research on Alzheimer Disease.

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).

Additional information

Funding

This work was supported by the Italian Ministry of Health under Grants RF-2010-2313220, RF-2011-02351193, and GR-2013-02357415; the European Research Council under Grant StG-2016_714388_NeuroTRACK; and the Foundation Research on Alzheimer Disease.