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

Abstract

Purpose: To evaluate the electro-clinical features in association with laboratory and instrumental correlates of neurodegeneration to detect the progression of Lafora disease (LD).

Methods: We investigated the electro-clinical longitudinal data and CSF Aβ42, p-tau₁₈₁ and t-tauAg, amyloid, and ¹⁸F-FDG PET of five unrelated LD families.

Results: Three 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.

Conclusions: Three 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.

Keywords: 18F-FDG PET; Lafora disease; amyloid biomarkers; electro-clinical features; follow-up; neurodegenerative biomarkers; progressive myoclonic epilepsy.

Figure 1

The electroclinical phases of LD patients. Four main and progressive symptoms (epilepsy, myoclonus, ataxia, and dementia) are included in three evolutive electroclinical stages [green line: Phase 1 (early stage); orange line: Phase 2 (intermediate stage); red line: Phase 3 (late stage)].

Figure 2

Aβ42, p-tau₁₈₁, t-tauAg values, and IATI, and graphics of Aβ42, p-tau₁₈₁, and t-tauAg visualization, and combination. According to the IATI index, the patients analyzed at the early stage showed a normal cognitive pattern profile (p-tau₁₈₁ < 60 pg/ml and IATI > 1.2), while the patients at the intermediate and late stages showed a pattern of non-Alzheimer dementia (ptau₁₈₁ < 60 pg/ml and IATI < 1.2).

Figure 3

SPM patient 1 longitudinal analysis (p = 0.05 cluster-level above 100 voxels). SPM-t maps showed FDG hypometabolism in Phase 2 (A) and Phase 3 after 18 months (B).

Figure 4

SPM patient 1 in Phase 2 of the disease (p = 0.05 cluster-level above 100 voxels). SPM-t maps show bilateral FDG hypometabolism within the thalamus and the temporal and frontal lobes.