Characterization of spastic paraplegia in a family with a novel PSEN1 mutation

Spastic paraparesis has been described to occur in 13.7% of PSEN1 mutations and can be the presenting feature in 7.5%. In this paper, we describe a family with a particularly young onset of spastic paraparesis due to a novel mutation in PSEN1 (F388S). Three affected brothers underwent comprehensive imaging protocols, two underwent ophthalmological evaluations and one underwent neuropathological examination after his death at age 29. Age of onset was consistently at age 23 with spastic paraparesis, dysarthria and bradyphrenia. Pseudobulbar affect followed with progressive gait problems leading to loss of ambulation in the late 20s. Cerebrospinal fluid levels of amyloid-beta, tau and phosphorylated tau and florbetaben PET were consistent with Alzheimer's disease. Flortaucipir PET showed an uptake pattern atypical for Alzheimer's disease, with disproportionate signal in posterior brain areas. Diffusion tensor imaging showed decreased mean diffusivity in widespread areas of white matter but particularly in areas underlying the peri-Rolandic cortex and in the corticospinal tracts. These changes were more severe than those found in carriers of another PSEN1 mutation, which can cause spastic paraparesis at a later age (A431E), which were in turn more severe than among persons carrying autosomal dominant Alzheimer's disease mutations not causing spastic paraparesis. Neuropathological examination confirmed the presence of cotton wool plaques previously described in association with spastic parapresis and pallor and microgliosis in the corticospinal tract with severe amyloid-beta pathology in motor cortex but without unequivocal disproportionate neuronal loss or tau pathology. In vitro modelling of the effects of the mutation demonstrated increased production of longer length amyloid-beta peptides relative to shorter that predicted the young age of onset. In this paper, we provide imaging and neuropathological characterization of an extreme form of spastic paraparesis occurring in association with autosomal dominant Alzheimer's disease, demonstrating robust diffusion and pathological abnormalities in white matter. That the amyloid-beta profiles produced predicted the young age of onset suggests an amyloid-driven aetiology though the link between this and the white matter pathology remains undefined. Ringman et al. describe three affected family members with a novel PSEN1 mutation with spastic paraparesis with onset at age 23. They describe atypical amyloid-beta pathology with imaging and neuropathological evidence of disproportionate effects on corticospinal tracts and found that the F388S mutation causes increased longer length amyloid-beta fragments to be produced.