ABSTRACT
INTRODUCTION: This study investigates primary lateral sclerosis (PLS) as a rare manifestation of the presenilin 1 (PSEN1) NM_000021 c.851C > T p.Pro284Leu variant in three siblings of a Colombian family, outlining its clinical and neuropathological features and their relationship to Alzheimer's disease (AD). METHODS: Data were gathered using clinical evaluations, next-generation genetic sequencing, magnetic resonance imaging, biomarker analysis, and neuropathological examination. RESULTS: Carriers of the PSEN1 Pro284Leu variant exhibited classic PLS symptoms, including unilateral onset and bulbar syndromes, along with cognitive decline. Neuropathology showed corticospinal tract degeneration without amyloid beta deposition in spinal white matter. DISCUSSION: Our findings suggest an overlap between PLS and AD pathology in PSEN1 variant carriers. Results support considering PLS when diagnosing AD-related motor syndromes and including PSEN1 evaluation when performing genetic testing for PLS. The study highlights the need for further research to clarify the PLS-AD relationship, informing future treatments and clinical trials. HIGHLIGHTS: Pathogenic variants in presenilin 1 (PSEN1) can manifest as hereditary primary lateral sclerosis PSEN1 Pro284Leu carriers present motor, cognitive, and behavioral alterations Cases had corticospinal tract microgliosis and severe Aß pathology in motor cortex There was no evidence of amyloid deposition in the spinal cord white matter All the neuropathology images are available for online visualization Myelin pallor in the spinal cord is confined to the lateral corticospinal tracts.
ABSTRACT
Short-term memory binding is a memory function that underpins the temporary retention of complex objects (e.g. shapes with colours). In the verbal domain, this function has been found to be impaired in sporadic Alzheimer's disease. Whether short-term memory binding is also impaired in familial Alzheimer's disease, whether this impairment extends to the visual domain and whether it could be detected earlier than other cognitive deficits are issues yet to be investigated. Twenty two patients with familial Alzheimer's disease caused by the E280A single presenilin-1 mutation, thirty carriers of the mutation who did not meet Alzheimer's disease criteria (asymptomatic carriers) and 30 healthy relatives (non-carrier healthy controls) were assessed with a visual short-term memory task and a neuropsychological battery. The short-term memory task assessed the recognition of shapes, colours or shape-colour bindings presented in two consecutive arrays (i.e. study and test). Changes, which always occurred in the test array, consisted of new features replacing studied features (single feature conditions) or of features swapping across items (the binding condition). The neuropsychological battery comprised tests of associative and non-associative memory, attention, language, visuospatial and executive functions. Patients with Alzheimer's disease and asymptomatic carriers performed significantly worse than healthy controls in the feature binding condition only. Group comparisons between asymptomatic carriers and healthy controls on standard neuropsychological tasks revealed no significant differences. Classification and area under the curve analyses confirmed that the binding task combines more sensitivity and specificity for patients with Alzheimer's disease and most notably for asymptomatic carriers of the mutation than other traditional neuropsychological measures. This suggests that visual short-term memory binding deficits may be a preclinical marker for familial Alzheimer's disease.