Association of CSF and PET markers of neurodegeneration with electroclinical progression in Lafora disease

Abstract

PurposeTo evaluate the electro-clinical features in association with laboratory and instrumental correlates of neurodegeneration to detect the progression of Lafora disease (LD).MethodsWe investigated the electro-clinical longitudinal data and CSF Aβ42, p-tau181 and t-tauAg, amyloid, and 18F-FDG PET of five unrelated LD families.ResultsThree progressive electro-clinical stages were identified. The early phase was characterized by rare, generalized tonic-clonic and focal visual seizures, followed by the occurrence of myoclonus after a period ranging from 2 to 12 months. The intermediate stage, usually occurring 2 years after the onset of epilepsy, is characterized by a worsening of epilepsy and myoclonus associated with progressive dementia and cerebellar signs. Finally, the late stage, evolving after a mean period of 7 ± 1.41 years from the onset of the disease, was characterized by gait ataxia resulting in bedriddenness, severe dementia, daily/pluri-daily myoclonus, drug-resistant epilepsy, clusters of seizures or status epilepticus, and medical complications. Amyloid (CSF Aβ42, amyloid PET) and neurodegenerative (CSF p-tau181 and t-tauAg, FDG-PET) biomarkers indicate a pattern of cognitive impairment of the non-Alzheimer's disease type. A total of 80% of the LD patients showed more severe hypometabolism in the second FDG-PET scan compared to the first scan performed in a lower phase; the lateral temporal lobe and the thalamus hypometabolism were associated with the presence of intermediate or late phase.ConclusionsThree electroclinical and 18F-FDG PET evolutive stages are useful biomarkers for the progression of LD and could help to evaluate the efficacy of new disease-modifying treatments. The combination of traditional CSF biomarkers improves the diagnostic accuracy of cognitive decline in LD patients, indicating a cognitive impairment of the non-Alzheimer's disease type.

Val-1221 for the Treatment of Patients With Lafora Disease: Study Protocol for a Single-Arm, Open-Label Clinical Trial

“…Additionally, we decided to include additional outcomes measures not assessed in the natural history study that might be helpful in providing evidence of VAL-1221 activity. These include brain FDG-PET, which has been shown to be highly sensitive to evaluate LD at any stage and may correlate with disease progression (Muccioli et al, 2020, d’Orsi et al, 2023), as well as neuropsychological tests assessing frontal lobe-related functions, such as executive functions, which are predominantly involved in LD (Pichiecchio et al 2008).…”