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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.
ABSTRACT
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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.
INTRODUCTION
DEMENTIA is associated with a variety of degenerative brain processes
that lead to distinct patterns of cognitive and behavioral decline.1 Occasionally, individuals demonstrate unusual patterns
of cognitive decline or may lack the pathophysiology of known diseases, raising
the question of an idiopathic or previously unknown dementing process. We
have been observing a family in upstate New York in which a number of individuals
have an unusual dementia associated with the presence of neuronal inclusion
bodies (Collins bodies) that are composed primarily of neuroserpin, a brain-specific
serine protease inhibitor (serpin).2
In 1989, the brain of a 65-year-old man with an unusual dementia characterized
by odd behaviors and cognitive deficits suggestive of Huntington disease was
brought for autopsy at the State University of New York Upstate Medical University,
Syracuse. Neuropathological examination disclosed the presence of round, 5-
to 50-µm eosinophilic inclusions of a previously unknown type detected
with hematoxylin-eosin stain (Figure 1).
The inclusions, which we later named Collins bodies,
were found scattered throughout the cerebral cortex and subcortical structures
but not in white matter. Their most significant concentrations were in the
deeper cortical layers (primarily pyramidal layers III-V), the insular cortex,
the cingulate gyrus, and the substantia nigra (pars compacta). The cerebellum
appeared to be spared.3
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Figure 1. Collins bodies. Formalin-fixed,
paraffin-embedded tissue from the frontal lobe (hematoxylin-eosin, original
magnification x400).
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The possibility of a familial dementia was raised after postmortem examination
of a second family member, who had also exhibited unusual behavior, showed
a similar distribution of Collins bodies. Investigation of the family confirmed
that other members had experienced similar neuropsychological problems. Affected
family members were described by their relatives as demonstrating perseveration,
poor judgment, lack of insight, memory difficulties, and eventual loss of
daily living skills. Other neurologic manifestations, including tremor, myoclonus,
limb dyspraxia, and cogwheel rigidity, were seen in the most severely affected
individuals.
Further investigation revealed that another affected family member,
a 55-year-old woman, had previously undergone neuropsychological testing in
1990. At the time of testing, she was described as restless and fidgety, with
impaired attention and response regulation and marked perseveration. Her word
finding was restricted on an object-naming measure, and her visuomotor functioning
was grossly impaired. Although her visual learning and memory were impaired,
she demonstrated intact verbal learning and memory. She received a diagnosis
of dementia, but Alzheimer disease was ruled out because of her relatively
intact verbal memory (Norman Lesswing, PhD, written communication, January
18, 1990). Results of postmortem examination showed Collins bodies with a
distribution similar to that found in her relatives.3
The Collins bodies were isolated from autopsy material from this woman
and were found to be composed primarily of neuroserpin. The DNA from this
sample was analyzed for changes in the neuroserpin gene (PI12), and a single point mutation was found, ie, a T-to-C transition
at nucleotide 226, which translates into a substitution of proline for serine
at amino acid position 49. Subsequently, DNA from 38 family members was isolated
from white blood cells and screened; the mutation was found in 14. Results
of genetic analysis showed an autosomal dominant linkage between the mutation
and the clinical presentation of dementia.4
We named the disease familial encephalopathy with
neuroserpin inclusion bodies (FENIB) and proposed that it is caused
by the polymerization and aggregation of the mutant neuroserpin protein into
Collins bodies. The objective of the present study is to describe the cognitive
and neuropsychological changes that accompany the clinical presentation of
FENIB.
SUBJECTS AND METHODS
SUBJECTS
Nine volunteer subjects (5 women, aged 31-64 years; 4 men, aged 43-67
years) from 2 generations of family members were studied. Genotyping indicated
that 6 subjects carried the gene for the mutation, whereas 3 did not. Subjects'
symptoms, by self-report and reports of other family members, ranged in severity
from asymptomatic to severe dementia. Subjects who were described as asymptomatic
by other family members were usually in their fourth and fifth decades of
life. One 67-year-old man was described as asymptomatic and subsequently found
to be free of the disease mutation. Subjects who demonstrated symptoms noticeable
to themselves and/or to other family members were older than 50 years. All
subjects were in relatively good physical health. Only 1 of the 9 subjects
recruited presented with obvious marked dementia during the clinical interview.
That subject, a 64-year-old woman, was unable to undergo testing on many of
the neuropsychological measures, and therefore her neuropsychological test
results were not included in the statistical comparison.
TEST INSTRUMENTS
Neuropsychological Assessment
Each subject was administered a 3- to 4-hour battery of neuropsychological
measures in accordance with published testing guidelines. The psychometric
tests used have been standardized to age-specific populations unless otherwise
noted. The tests evaluated a broad range of neuropsychological functions and
are listed in Table 1.
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Table 1. Neuropsychological Test Instruments*
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Magnetic Resonance Imaging
Cross-sectional T1- and T2-weighted magnetic resonance imaging (MRI)
scans of the brain were acquired using a 1.5-T superconducting magnetic imaging
unit (Siemens Medical Systems, Inc, Iselin, NJ) to detect the presence of
morphologic brain changes.
Single-Photon Emission Computed Tomography
Cross-sectional images of regional cerebral blood flow (rCBF) in the
brain were acquired by means of single-photon emission computed tomography
(SPECT) over 20 minutes using a 3-head scanner (Triad; Trionix, Twinsburg,
Ohio) to detect  -radiation emitted from intravenously administered
technetium Tc 99m bicisate. Three-dimensional images of brain rCBF were reconstructed
from the acquired data. Before the injection of the tracer, subjects lay quietly
in a dimly lit room for about 10 minutes and were instructed to relax. They
received no instructions to perform any cognitive tasks during the administration
of the tracer.
Electroencephalography
The electroencephalographic (EEG) recordings were made using a digital
acquisition system (Grass-Telefactor, a division of Astro-Med, Inc, West Warwick,
RI) using 21 recording channels and a 10-20 electrode placement system. Subjects
underwent testing in awake and drowsy conditions that included photic stimulation
and hyperventilation.
ANALYSIS
Results of MRI, SPECT, and EEG were interpreted by physicians in the
Departments of Radiology, Division of Nuclear Medicine, and Neurology, respectively,
State University of New York Upstate Medical University, according to standard
protocols. The results of those measures were binomially classified as indicating
the absence or presence of abnormalities. The MRI, EEG, and SPECT findings
of subjects carrying the mutation were compared with the findings of those
who did not using the Fisher exact test.
Neuropsychological tests were scored according to the guidelines provided
in their respective test manuals. On most measures, subject test scores were
obtained using the normative data from normally distributed age-specific general
populations provided in the test manuals. In most cases, neuropsychological
test scores were converted to standard scores (mean, 100; SD, 15). Some tests
assessing frontal lobe–dependent functions, including alternating hand
movements, reciprocal motor programs, and repeating graphomotor patterns (cursive m's and n's), were not readily
converted to standard scores. This was also true for some language tests (subtests
of the Boston Diagnostic Aphasia Examination). Those test results were classified
instead on a 4-point scale of impairment. The Stroop color-word interference
test scores were not standardized, and instead raw error scores were used
for the between-group comparison.
We computed z-score comparisons between the
mean standardized test scores of the mutation-present family members and the
mean scores of the population on which the tests were normed (mean score,
µ = 100) to determine statistically significant differences between
the affected subjects and the general population. Significant z scores indicate significantly lower mean scores in the mutation-present
group compared with the general population.
We also compared the scores of the mutation-present family members with
the mutation-absent family members to control for possible nonspecific familial
factors. Because of the small and unequal subject group sizes, Aspin-Welch
1-tailed t tests were used to compare the test scores
of mutation-present and mutation-absent groups. Post hoc power analyses of
comparisons that reached or approached significance were completed using an
online power calculator available from the Department of Statistics, University
of California–Los Angeles.7
RESULTS
Table 2 shows statistically
significant z scores that indicate areas of impaired
neuropsychological functioning in the mutation-present group. Significant
deficits were found on measures of attention and concentration (Wechsler Memory
Scale–Revised Attention/Concentration Index8),
oral fluency to generate lists of words beginning with particular letters
(f, a, and s5), and word-list learning (California
Verbal Learning Test9). Near significance was
found on measures of visuospatial reasoning (Wechsler Adult Intelligence Scale–Revised
[WAIS-R] Performance IQ10; P = .10). The z scores were not obtained on
the Stroop Color-Word Interference Test,11
which measures inhibition of an impulsive tendency to read words rather than
to perform an alternative response, because subject performance was not normally
distributed. Nonetheless, the performance of the mutation-present group was
clinically impaired, particularly in the more severely affected subjects who
demonstrated marked difficulty inhibiting their automatized reading response.
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Table 2. Areas of Impaired Neuropsychological Functioning*
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Table 3 shows between-group
comparisons of the neuropsychological test scores of the mutation-present
and mutation-absent groups. Aspin-Welch 1-tailed t
tests indicated significant differences (P<.05)
between groups on the same measures on which the mutation-present population
differed from the normal population, with the exception of the California
Verbal Learning Test, indicating that the restricted verbal learning by the
mutation-present group was not unique to that group and could not be attributed
to the effects of the gene mutation alone. A near-significant difference (P = .08) was found on the Stroop Color-Word Interference
Test.11 Near-significant differences were also
found on measures of visuospatial reasoning (WAIS-R Performance IQ10; P = .07) and visual encoding
(Wechsler Memory Scale–Revised Visual Reproduction8; P<.08). Overall, power analyses indicated relatively
low power for the individual comparisons due to the small sample size and
the large variance. The relatively low power of the comparisons, even using
a substantial effect size in the computations, supported the use of multiple
1-tailed t tests to increase the chances of detecting
an effect. Low power also reflects the need to interpret lack of significant
findings cautiously because of a greater chance of type II error.
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Table 3. Between-Group Comparisons of Neuropsychological Test Scores*
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In the comparisons between mutation-present and mutation-absent family
members, age effects were not statistically significant, which was not surprising
given the small sample sizes of both groups. Clinically, however, the youngest
mutation-present subjects demonstrated the least impairment on the neuropsychological
measures compared with the older mutation-present subjects. The oldest subjects
carrying the mutation were the most severely affected and demonstrated the
most global dementia with prominent frontal lobe features.
On the physiological measures (MRI, SPECT, and EEG), differences between
the mutation-present and mutation-absent groups were not statistically different,
but marked qualitative changes were clinically observed in the affected group.
First, SPECT rCBF anomalies were present and were limited to frontal areas
in the less affected subjects but were more global, with patchy areas of hypoperfusion
in the more severely affected subjects (Figure
2). Second, EEG findings revealed global slowing in the 3 most severely
affected (and oldest) subjects. Finally, MRI findings were revealing in only
the 2 most severe cases; both showed global cortical atrophy.
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Figure 2. Single-photon emission computed
tomographic brain scans of 3 subjects in a resting state normalized to the
same maximal value. A, Transverse images from an unaffected (mutation-absent)
family member showing normal cortical perfusion. B, Images from a mildly affected
subject with areas of moderately well-preserved prefrontal cortex and some
areas of cortical hypoperfusion denoted by arrows. C, Images from a more severely
affected subject demonstrating more global areas of hypoperfusion. Window
and centering of data is from pixel values of 171 (0%) to 511 (100%).
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One subject, a man in the seventh decade of life who did not carry the
mutation, showed nonspecific white matter changes and mild global atrophy
on MRI findings. This subject also showed mildly slowed and disorganized EEG
findings and rCBF deficits on SPECT findings. Cerebrovascular disease was
suspected. His scores on neuropsychological measures were within normal limits,
with the exception of impaired performance on the Boston Naming Test, which
was not an area of impairment for the mutation-carrying group.
COMMENT
The cognitive deficits that accompany FENIB are qualitatively unique
when compared with the patterns of progressive decline associated with other
dementing processes. The FENIB-affected subjects consistently demonstrated
deficits in areas associated with frontal lobe processes. Subjects carrying
the gene mutation who were initially described as asymptomatic demonstrated
mostly intact cognition, with the exception of restricted attention, concentration,
and oral fluency, ie, an inability to generate lists of words beginning with
particular letters (f, a,
and s). Because the frontal lobes and related frontal-subcortical
structures are regions of the brain that are intimately associated with attention,12 the subjects' attention deficits suggest that the
accumulation of Collins bodies primarily affects frontal and frontal-subcortical
areas during the early stages of the disease process. Deficits in oral fluency
also implicated frontal areas, because oral fluency is also dependent on intact
frontal lobe functioning.13 The findings of
SPECT perfusion deficits in the frontal lobes in the mildly affected subjects
with FENIB also indicated frontal lobe involvement early in the course of
the disease.
As the disease progresses, cognitive deficits become more global in
nature, presumably because of an increased accumulation of Collins bodies.
In addition to restricted attention and fluency, the more affected subjects
demonstrated impaired visuospatial organization. The most severely affected
subjects demonstrated more marked deficits in frontal lobe–related areas
of attention, concentration, mental control, working memory, and response
regulation, and they exhibited impaired verbal and visual reasoning and restricted
expressive and receptive language. Finally, the most significantly affected
subject demonstrated severe dementia with prominent frontal features (eg,
perseveration, stereotypic behavior, stimulus-bound behavior, and motor restlessness).
Of note is that the most affected subjects demonstrated some sparing of recall
memory when provided structure to assist in their recall such as cues or forced-choice
recognition.
The findings of frontal lobe–related cognitive deficits and marked
accumulation of Collins bodies in the substantia nigra in FENIB suggest similarities
to Parkinson disease, which is characterized by the accumulation of Lewy bodies
and neurodegeneration in this same region. Likewise, the early manifestation
of attention, concentration, and fluency deficits and the subsequent emergence
of restricted visuoconstructional reasoning (indicated by lower WAIS-R Performance
IQ scores) in FENIB are qualitatively similar to cognitive deficits described
for Parkinson disease.6, 14 However,
the marked motor involvement and cognitive slowing that typically accompany
Parkinson dementia are not primary characteristics of FENIB. Hence, the 2
diseases can be clearly differentiated.
Furthermore, the dementia associated with FENIB is qualitatively distinct
from dementia of the Alzheimer type (DAT) and from other "cortical" dementias
(ie, dementias with a characteristic decline of cortically dependent functions
such as language, reasoning, and memory). The relative sparing of recall memory
and the lack of significant word-finding difficulty on testing, both of which
are hallmarks of early DAT,15 are spared in
the early stages of FENIB and indicate that it is clinically distinct from
DAT. The neurophysiological changes underlying the differences between FENIB
and other dementing processes directly affecting the cortex are not clear,
since many of these disorders also have characteristic cortical inclusions.
One possible explanation may be that in FENIB the inclusions (ie, Collins
bodies) are found mostly in the deeper cortical layers (III-V).
A number of frontotemporal dementias have been described, some of which
are associated with chromosome 17q21.16, 17, 18, 19
Although different frontotemporal dementia syndromes have been described,
common characteristics among them include middle-age onset, cognitive deficits
associated with frontal lobe functioning, memory deficits, and Parkinsonlike
motor involvement. Although FENIB shares a number of these characteristics,
its histopathologic features and molecular genetics make it distinct from
other frontotemporal dementia syndromes.
Age appears to play a vital role in the clinical manifestations of FENIB,
although age differences did not achieve statistical significance because
of our limited sample size. We assume that the emergence of cognitive deficits
correlates with the deposition of neuroserpin as Collins bodies in the brain.
Generally, problems are not noticeable by other family members until the affected
individuals reach their fifth or early sixth decade of life. Conversely, neuropsychological
testing demonstrates changes at an earlier age. For example, in our study,
2 mutation-present subjects in their early fourth decades of life showed cognitive
deficits. In one subject, the changes were subtle and were restricted to limited
learning of a word list with intact learning on other memory tasks, whereas
the other showed more notable cognitive decline. As an individual ages, the
disease becomes clinically recognizable; the 2 mutation-present subjects in
their fifth decade of life showed marked deficits, whereas the subject in
his sixth decade of life was clearly demented, and the oldest subject, who
was in her seventh decade of life, was nearly unable to undergo testing. The
late onset of FENIB thus conforms to the general pattern of neurodegeneration
caused by aberrant protein processing and tissue deposition. Because neurons
are nondividing cells, the damage appears to be cumulative and irreversible.
The question of familial factors unrelated to the gene mutation that
may have influenced subjects' cognition in our study was raised by our finding
that mutation-present and mutation-absent family members demonstrated impaired
learning on a word-list learning test. The finding of impaired performance
by the control group on that measure indicated that the low scores of the
mutation-present family members on that measure could be attributed to nonspecific
or familial factors other than FENIB. Thus, caution must be taken when interpreting
cognitive deficits of FENIB without adequate control subjects.
Recently, other occurrences of FENIB have been described in which the
patients present with epilepsy and dementia.20, 21, 22
The findings of FENIB in unrelated families suggests that neuroserpin may
play a more widespread role in dementia than previously known. Further study
of individuals carrying the gene mutation in the family that we have been
observing and in others as they may be discovered will provide better understanding
of the progression of cognitive loss secondary to the accumulation of neuroserpin
in the brain. Technological advances suggest that measures to quantify neuroserpin
concentrations will become available, such as the development of MRI spectroscopy
protocols. New means of evaluating the presence of neuroserpin in the brain
will allow researchers to correlate neuroserpin accumulation with physiological
and neuropsychological measures to provide further understanding of the disease
process and its effects on cognition.
AUTHOR INFORMATION
Accepted for publication April 11, 2001.
We gratefully acknowledge the support of grant AG16954 from the National
Institutes of Health, Bethesda, Md.
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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