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

Abstract

ObjectiveTo 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).MethodsThis 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.ResultsOf 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.ConclusionOur 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.

The Characteristics of Cognitive Impairment in ALS Patients Depend on the Lateralization of Motor Damage

“…Our findings point out that cognitive features of ALS patients are related to motor impairment and follow hemispheric lateralization, suggesting a possible disease spreading or simultaneous degeneration of highly interconnected frontal and precentral neurons. In keeping with previous studies, we have found that patients with bulbar onset are generally more cognitively impaired than those with spinal onset [8]. However, when we subdivided patients not only according to the site of onset (bulbar vs. spinal), but also according to the side of onset, we found that spinal patients with symmetric motor impairment have significantly worse cognitive performance than those with lateralized damage, and appear to have a cognitive dysfunction similar to bulbar patients.…”

“…Since the description of the ALS-FTD spectrum [16], the interconnection between motor and cognitive impairment has become one of the main topics in the ALS research field. Recent findings have pointed out that the extension of motor impairment, measured using King's and MiToS clinical staging systems, is correlated with cognitive decline [8]. Despite this, the complex mechanisms underlining their relationship are far from being fully understood and probably only in vivo neurodegeneration monitoring through neuroimaging could help to solve this problem [17].…”

“…Cognitive impairment is a frequent additional feature of ALS [5,6], being mainly related to frontotemporal cortical neuron degeneration, such as motor impairment. There are indications that cognitive function may worsen during disease progression [7], with a correlation to motor dysfunction and clinical stages [8].…”

Regional spreading of symptoms at diagnosis as a prognostic marker in amyotrophic lateral sclerosis: a population-based study

“…Cognitive impairment has been widely recognised as one of the major determinants of disease outcome 6. Recent findings suggested that ALS motor and cognitive components may worsen in parallel during disease progression 20. In our sensitivity analysis with NBRI-C, we found an exponential increase in risk across categories, confirming that the spread of the disease through cognitive areas is a cause of worse prognosis, independently from specific motor impairment.…”

“…Neuropsychological evaluation was performed at diagnosis (diagnosis-evaluation interval ≤3 months) in 622 patients (58.6%). Patients’ cognitive status was classified according to the revised amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTD) Consensus Criteria19: the neuropsychological batteries used for classification were described in our previous work 20. To evaluate the effect of cognitive impairment, we subdivided patients into two categories: cognitively impaired patients (corresponding to ALS-FTD, ALSbi, ALSci, ALScbi categories in the revised ALS-FTD Consensus Criteria) and cognitively normal patients (corresponding to ALS-CN category).…”