9. Upper motor neuron dysfunction and neuropsychological profile in PLS: Another entrant on the ALS-FTD spectrum

Abstract

Background Primary lateral sclerosis (PLS), a rare upper motor neuron disorder, remains a debated entity as an upper motor neuron extreme form of amyotrophic lateral sclerosis (ALS) or a distinct disease. It is now well established that ALS and frontotemporal dementia (FTD) lie on two ends of the frontal neurodegenerative spectrum. While early descriptions of PLS excluded cognitive dysfunction, there is accumulating evidence of varying degrees of frontal lobe deficits accompanying structural and functional changes in the brain in PLS. Methodology This study examined the neurophysiological features using transcranial magnetic stimulation (TMS) and neuropsychological profile in a cohort of patients (n = 21) with PLS. Clinical, neuropsychological and TMS findings in PLS patients were compared with two distinct cohorts of patients who had pure ALS (n = 27) and ALSFTD (n = 12). Multivariable regression analysis was used to examine independent predictors of global cognitive function on the Addenbrooke’s cognitive examination (ACE) score and motor disability on the ALS functional rating scale (ALSFRS). Kaplan Meier curves were used to determine survival times for the three groups. Results Mean age in PLS was 60.9 ± 10.4, 47.6% of patients were males and 95% had limb onset disease. The mean survival time was longest in PLS (217.43 ± 22.4 months) and shortest in ALSFTD (38.54 ± 4.5 months). In addition to prominent upper motor neuron (UMN) dysfunction, ACE score was impaired in PLS (mean total ACE score 82.5 ± 13.6), lying intermediately between pure ALS (mean total ACE score 93.4 ± 3.9) and ALSFTD (mean total ACE score 76.3 ± 7.7). Behavioural impairments were not prominent in PLS as indicated by a higher total Motor Neuron Disease Behaviour (MiND-B) score than ALSFTD (PLS 32.1 ± 5.6, ALSFTD 22.4 ± 6.8, p = 0.005). In terms of cortical function, resting motor threshold (RMT) was significantly higher in PLS (93.2 ± 11.7, p RMT predicted higher global cognition score on the ACE ( β = 0.57, p = 0.001), independent of motor progression and clinical upper motor neuron dysfunction. Average SICI predicted motor disability ( β = 0.5, p = 0.008), on the ALS functional rating scale (ALSFRS), independent of disease duration and upper motor neuron score across the three groups. Conclusions There is a distinctive cognitive profile in PLS which resembles ALSFTD, without the behavioural disturbances typical of the FTD spectrum disorders. Cortical motor neuronal hyperexcitability was associated with poorer global cognitive function, independent of motor disease progression, while dysfunction of inhibitory interneuronal circuits predicted motor disability, across ALS, ALSFTD and PLS. Overall, these findings make a strong case for PLS being on the ALS FTD spectrum and suggest that cortical excitability contributes to neuropsychological and motor dysfunction by distinct pathophysiological mechanisms.