Cognitive deficits associated with a recently reported familial neurodegenerative disease - Familial encephalopathy with neuroserpin inclusion bodies

Background: We recently discovered an autosomal dominant disease causing a progressive dementia. The disease is caused by a point mutation in the gene coding for the serine protease inhibitor (ie, serpin) neuroserpin. The mut ation results in an unstable neuroserpin protein that readily aggregates in to intraneuronal inclusions that we identify as Collins bodies. The bodies are distributed throughout the cerebral hemispheres but are significantly m ore numerous in the cortex and the substantia nigra. We have named the dise ase familial encephalopathy with neuroserpin inclusion bodies (FENIB), Objectives: To describe the cognitive and neurophysiological changes exhibi ted by individuals with FENIB and to correlate the phenotypic expression of the disease with the neuropathological findings. Design: Multiple case studies using neuropsychological assessment, electroe ncephalography (EEG), magnetic resonance imaging (MRI), and single-photon e mission computed tomographic (SPECT) studies of family members were perform ed. Using these measures, we also compared family members in whom the mutat ion is present with family members in whom the mutation was absent to contr ol for nonspecific familial factors. Subjects: Nine individuals (5 women, aged 31-64 years; 4 men, aged 43-67 ye ars) from 2 generations of family members related to the first reliably ide ntified individual with symptoms of this disease. Symptoms, by self-report and reports of other family members, ranged from asymptomatic to severe dem entia. Six of the 9 individuals carried the disease mutation. Results: All subjects with the mutation demonstrated some cognitive changes , with the greatest demonstrated by subjects older than 40 years. The chang es included restricted attention, concentration, and response regulation fu nctions, reduced controlled oral fluency (word-list generation), and restri cted visuospatial organization. In general, recall memory was not as affect ed as other cognitive domains. The most severely affected subject demonstra ted global dementia with prominent frontal lobe features. Findings on SPECT showed anomalies limited to frontal areas in the less affected subjects an d more global, patchy areas of hypoperfusion in the more severely affected subjects. The 3 oldest and most affected subjects demonstrated slowing on E EG findings. The MRI findings were noncontributory except in the 2 most sev ere cases, which showed global cortical atrophy. Conclusions: Cognitive changes in mildly to moderately affected subjects we re characterized by deficits in frontal and frontal-subcortical area-depend ent processes. Continued progressive deterioration of cerebral functions wi th relative sparing of recall memory suggests a unique dementia associated with this disease.