Cognitive dysfunction in amyotrophic lateral sclerosis: can we predict it?

Abstract

Background and aim Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motoneurons in the brain and spinal cord leading to motor and extra-motor symptoms. Although traditionally considered a pure motor disease, recent evidences suggest that ALS is a multisystem disorder. Neuropsychological alterations, in fact, are observed in more than 50% of patients: while executive dysfunctions have been firstly identified, alterations in verbal fluency, behavior, and pragmatic and social cognition have also been described. Detecting and monitoring ALS cognitive and behavioral impairment even at early disease stages is likely to have staging and prognostic implications, and it may impact the enrollment in future clinical trials. During the last 10 years, humoral, radiological, neurophysiological, and genetic biomarkers have been reported in ALS, and some of them seem to potentially correlate to cognitive and behavioral impairment of patients. In this review, we sought to give an up-to-date state of the art of neuropsychological alterations in ALS: we will describe tests used to detect cognitive and behavioral impairment, and we will focus on promising non-invasive biomarkers to detect pre-clinical cognitive decline. Conclusions To date, the research on humoral, radiological, neurophysiological, and genetic correlates of neuropsychological alterations is at the early stage, and no conclusive longitudinal data have been published. Further and longitudinal studies on easily accessible and quantifiable biomarkers are needed to clarify the time course and the evolution of cognitive and behavioral impairments of ALS patients.

Functional alterations in large-scale resting-state networks of amyotrophic lateral sclerosis: A multi-site study across Canada and the United States

“…Moreover, positive correlations with disease progression rate and symptom duration suggest higher neuronal synchronization is linearly associated with an average disease progression rate and severity of clinical symptoms [ 96 , 97 ]. Last, Rs-FC in the left fronto-parietal RSN was associated with cognitive performance (ECAS Total) indicating that the underlying neural mechanism might be analogous to the dysfunctions of frontal and parietal brain regions [ 79 , 98 – 101 ]. Overall, the present findings suggest that functional connectivity in the fronto-parietal network is crucial for instantiating and flexibly modulating cognitive control [ 102 ].…”

“…Moreover, higher intra-network Rs-FC in the auditory, medial temporal, and ventral stream RSNs negatively correlated with ALSFRS-R, indicating that physical impairment is associated with the altered neural connectivity accompanying the progression of loss in functional outcomes [ 105 , 125 ]. Higher intra-network Rs-FC in the medial temporal RSN also correlated negatively with ECAS Total and ECAS ALS Specific scores, indicating that greater medial temporal connectivity is associated with worse cognitive performance specifically involving language, verbal fluency, and executive functions [ 95 , 98 , 126 ]. The abnormal Rs-FC involving the mesial temporal lobe is in line with frontotemporal lobar degeneration.…”

The Need for Biomarkers in the ALS–FTD Spectrum: A Clinical Point of View on the Role of Proteomics

“…Notably, unlike what was believed in the past, ALS is not only a “motor disease”, but it is also frequently associated with extramotor symptoms, mainly behavioral and cognitive alterations. Cognitive impairment can occur early during the disease course, and it generally concerns 40–50% of people with ALS [ 6 ]. Cognitive deficits generally involve executive functions, attention, working memory, and organization dysfunction.…”

“…ALS is the most common motor neuron disease [ 4 ]; it is clinically characterized by motor dysfunction due to upper and lower motor neuron degeneration that leads to progressive paralysis and death from respiratory failure, usually within three-to-five years after the onset of symptoms [ 4 , 5 ]. Although motor dysfunction is the cardinal symptom of ALS, up to 50% of these patients developed cognitive impairment and, notably, roughly 15% of these patients presented clinical symptoms of FTD [ 6 ].…”

Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies

“…However, behavioral changes in patients with ALS include subtle changes in social cognition. These changes can be adequately measured with specific tests such as the Reading the mind in the eyes test or the faux-pas test ( 41 , 48 ). On the other hand, up to 15% of patients initially diagnosed with FTD may also develop motor neuron signs during follow-up ( 10 , 49 ).…”