Cognitive vulnerability to levodopa therapy in ataxia-telangiectasia patients: a psychophysiological study

Ataxia-telangiectasia (AT) is a human disease caused by mutations in the ATM gene. The neural phenotype of AT includes progressive cerebellar neurodegeneration, which results in ataxia, oculocutaneous teleangiectasias, immunodeficiency, recurrent infections, radiosensitivity and proneness to cancer. No therapies are available for this disease. Experimental studies on mice showed severe degeneration of tyrosine hydroxylase-positive, dopaminergic nigro-striatal neurons, and their terminals in the striatum. The aim of the current study was to investigate the effects of the levodopa therapy on motor and cognitive performance in AT patients using clinical and psychophysiological evaluation. 3 young AT-patients (age: 12 years) underwent a neurological evaluation and a CNV recording in basal condition (T0) and at two times points after levodopa therapy (at 4 weeks – T1 and 8 weeks – T2). MICARS and UPDRS III scales were administered in order to assess clinical performance and disability. CNV amplitude (total and in two different temporal windows – W1, W2) was evaluated. Reaction times were also obtained. Total CNV amplitude (T0 vs T2: Fz p=0,03; T1 vs T2: Fz p=0,05 Cz p=0.07), W1 (T0 vs T2: Fz p=0,06; T1 vs T2: Fz p=0,08) and W2-CNV areas (T0 vs T2: Fz p=0,05, Cz p=0,05, Pz p=0,05; T1 vs T2: Fz p=0,01, Cz p=0,04) were significantly higher after 8 weeks of levodopa therapy than during basal condition and at 4 weeks of levodopa therapy. UPDRSIII values significantly improved after 8 weeks of L-dopa therapy (T0 vs T2: p=0,004). Our data suggest that levodopa treatment led to a significant improvement in motor performance in AT patients. Additionally, the ability to sustain attention during a double choice motor task appears to ameliorate after levodopa therapy. These results induce us to hypothesize the presence of a dopaminergic dysfunction likely related to a possible involvement of the subcortical networks in AT subjects as suggested by experimental studies. Moreover, from a clinical point of view, these evidences support the potential role of levodopa in the treatment of individuals with ataxia telangiectasia.