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Cognitive Deficits Associated With a Recently Reported Familial Neurodegenerative Disease
Familial Encephalopathy With Neuroserpin Inclusion Bodies
Charles B. Bradshaw, PhD;
Richard L. Davis, MD, PhD;
Antony E. Shrimpton, PhD;
Peter D. Holohan, PhD;
Cornelia B. Rea, PhD;
David Fieglin, MD;
Paul Kent, MD, PhD;
George H. Collins, MD
Arch Neurol. 2001;58:1429-1434.
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 mutation results
in an unstable neuroserpin protein that readily aggregates into intraneuronal
inclusions that we identify as Collins bodies. The bodies are distributed
throughout the cerebral hemispheres but are significantly more numerous in
the cortex and the substantia nigra. We have named the disease familial encephalopathy
with neuroserpin inclusion bodies (FENIB).
Objectives To describe the cognitive and neurophysiological changes exhibited by
individuals with FENIB and to correlate the phenotypic expression of the disease
with the neuropathological findings.
Design Multiple case studies using neuropsychological assessment, electroencephalography
(EEG), magnetic resonance imaging (MRI), and single-photon emission computed
tomographic (SPECT) studies of family members were performed. Using these
measures, we also compared family members in whom the mutation is present
with family members in whom the mutation was absent to control for nonspecific
familial factors.
Subjects Nine individuals (5 women, aged 31-64 years; 4 men, aged 43-67 years)
from 2 generations of family members related to the first reliably identified
individual with symptoms of this disease. Symptoms, by self-report and reports
of other family members, ranged from asymptomatic to severe dementia. 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 changes
included restricted attention, concentration, and response regulation functions,
reduced controlled oral fluency (word-list generation), and restricted visuospatial
organization. In general, recall memory was not as affected as other cognitive
domains. The most severely affected subject demonstrated global dementia with
prominent frontal lobe features. Findings on SPECT showed anomalies limited
to frontal areas in the less affected subjects and more global, patchy areas
of hypoperfusion in the more severely affected subjects. The 3 oldest and
most affected subjects demonstrated slowing on EEG findings. The MRI findings
were noncontributory except in the 2 most severe cases, which showed global
cortical atrophy.
Conclusions Cognitive changes in mildly to moderately affected subjects were characterized
by deficits in frontal and frontal-subcortical area–dependent processes.
Continued progressive deterioration of cerebral functions with relative sparing
of recall memory suggests a unique dementia associated with this disease.
From the Departments of Neurology (Drs Bradshaw and Kent), Pathology
(Drs Davis, Shrimpton, and Collins), and Pharmacology (Dr Holohan) and the
Division of Nuclear Medicine, Department of Radiology (Dr Fieglin), State
University of New York Upstate Medical University, Syracuse; and the Department
of Psychology, State University of New York at Cortland (Dr Rea).
Corresponding author and reprints: Charles B. Bradshaw, PhD, Department
of Neurology, Upstate Medical University, 750 E Adams St, Syracuse, NY 13210.
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