Cognitive impairment across ALS clinical stages in a population-based cohort

Abstract

Objective: To assess the association of the degree of severity of motor impairment to that of cognitive impairment in a large cohort of patients with amyotrophic lateral sclerosis (ALS).

Methods: This is a population-based cross-sectional study on patients with ALS incident in Piemonte, Italy, between 2007 and 2015. Cognitive status was classified according to the revised ALS-FTD Consensus Criteria. The King system and the Milano Torino Staging system (MiToS) were used for defining the severity of motor impairment.

Results: Of the 797 patients included in the study, 163 (20.5%) had ALS-frontotemporal dementia (FTD), 38 (4.8%) cognitive and behavioral impairment (ALScbi), 132 (16.6%) cognitive impairment (ALSci), 63 (7.9%) behavioral impairment (ALSbi), 16 (2.0%) nonexecutive impairment, and 385 (48.2%) were cognitively normal. According to King staging, the frequency of cases with ALS-FTD progressively increased from 16.5% in stage 1-44.4% in stage 4; conversely, the frequency of ALSci, ALSbi, and ALScbi increased from King stage 1 to King stage 3 and decreased thereafter. A similar pattern was observed with the MiToS staging. ALS-FTD was more frequent in patients with bulbar involvement at time of cognitive testing. Patients with C9ORF72 expansion (n = 61) showed more severe cognitive impairment with increasing King and MiToS stages.

Conclusion: Our findings suggest that ALS motor and cognitive components may worsen in parallel, and that cognitive impairment becomes more pronounced when bulbar function is involved. Our data support the hypothesis that ALS pathology disseminates in a regional ordered sequence, through a cortico-efferent spreading model.

Figure 1. Flowchart reporting enrollment

Figure 2. Cognitive classification and King stage or Milano Torino Staging system (MiToS) stage

(A) Cognitive classification and King stage. Number of patients: King stage 1, 407; King stage 2, 219; King stage 3, 135; King stage 4, 36. (B) Cognitive classification and MiToS stage. Number of patients: MiToS stage 1, 584; MiToS stage 2, 189; MiToS stage 3, 24. ALS-CN = cognitively normal with amyotrophic lateral sclerosis; ALS-FTD = amyotrophic lateral sclerosis with a frontotemporal dementia syndrome; ALSbi = amyotrophic lateral sclerosis with behavioral impairment; ALScbi = amyotrophic lateral sclerosis with combined cognitive and behavioral impairment; ALSci = amyotrophic lateral sclerosis with cognitive impairment; ALSnex = amyotrophic lateral sclerosis with isolated nonexecutive impairment.

Figure 3. Cognitive classification and amyotrophic lateral sclerosis (ALS) staging according to the site of onset

(A) King staging, bulbar onset. (B) King staging, spinal onset. (C) Milano Torino Staging system (MiToS) staging, bulbar onset. (D) MiToS staging, spinal onset. ALS-CN = cognitively normal with amyotrophic lateral sclerosis; ALS-FTD = amyotrophic lateral sclerosis with a frontotemporal dementia syndrome; ALSbi = amyotrophic lateral sclerosis with behavioral impairment; ALScbi = amyotrophic lateral sclerosis with combined cognitive and behavioral impairment; ALSci = amyotrophic lateral sclerosis with cognitive impairment; ALSnex = amyotrophic lateral sclerosis with isolated nonexecutive impairment.

Figure 4. Cognitive classification and amyotrophic lateral sclerosis (ALS) staging according to the presence of bulbar symptoms at time of cognitive testing

(A) King staging, bulbar sign present. (B) King staging, no bulbar signs. There are no patients in King stage 3 in the group of participants without bulbar signs at time of cognitive testing, in accordance with the method of classification. (C) Milano Torino Staging system (MiToS) staging, bulbar sign present. (B) MiToS staging, no bulbar signs. ALS-CN = cognitively normal with amyotrophic lateral sclerosis; ALS-FTD = amyotrophic lateral sclerosis with a frontotemporal dementia syndrome; ALSbi = amyotrophic lateral sclerosis with behavioral impairment; ALScbi = amyotrophic lateral sclerosis with combined cognitive and behavioral impairment; ALSci = amyotrophic lateral sclerosis with cognitive impairment; ALSnex = amyotrophic lateral sclerosis with isolated nonexecutive impairment.