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CNS distribution of free-radical inactivating enzymes in amyotrophic lateral sclerosis.

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thors would try to fit their data into the framework that we
have outlined.
Alzheimer j. Disease Unit
Ospedale S.Cuore-FBF
Via Pilastroni 4, and
Geriatric Research Group
Via Romanino I
Brescia, Italy
References
1 . Gomez-Isla T, West HL, Rebeck GW, et al. Clinical and pathological correlates of apolipoprotein E ~4 in Alzheimer’s disease.
Ann Neurol 1996;39:62-70
2. Frisoni GB, Calabresi L, Geroldi C, et al. Gene dose of the
~4 allele of apolipoprotein E and gender in sporadic late-onset
Alzheimer’s disease. Ann Neurol 1995;37:596-604
3. Yesavage JA, Brooks JO. O n the importance of longitudinal
research in Alzheimer’s disease. J Am Geriarr Soc 1992;39:942944
Reply
Bradley T . Hyman, MD, PhD, Teresa Gomez-Isla, MD,
PhD, and John H. Growdon, MD
We appreciate the comments of Frisoni and associates [l],
regarding our study of the clinical and pathological correlates
of apolipoprotein E (APOE) genotype in Alzheimer’s disease
121. We agree that whether inheritance of APOE ~4 influences the clinical rate of progression in Alzheimer’s disease
is an important although complicated issue. Our data suggest
that APOE t 4 influences the average age of onset of dementia but does not alter the course of the illness thereafter. This
result was derived from a serial evaluation of 153 patients
for an average of 31.8
18.7 months [ 2 ] ,during the middle
stages of Alzheimer dementia, when the patients were living
at home and attending the outpatient neurology clinic. In
this phase of the illness, decline on the Blessed Dementia
Scale and on the Activity of Daily Living scales is linear, and
free from floor effects 131. Covarying gender, age of onset,
and initial degree of impairment did not alter this outcome.
In a subsequent more detailed study, we found that rate of
decline on a broad range of neuropsychometric tests were
not influenced by APOE genotype [4].Conclusions similar
to our report of finding no influence of APOE ~4o n rate
of progression of dementia have been found in several other
large series where rate of progression was assessed prospectively by serial examinations. For example, Dal Forno and
colleagues [5] followed 101 patients for more than 10 years
(average of 3.5 years) and concluded that APOE ~4 did not
consistently alter rate of change on cognitive scores. Waring
and collaborators [6] came to a similar conclusion based on
the Mayo Clinic experience of 132 Alzheimer‘s disease patients followed over 2.7 years.
It is uncertain how APOE t 4 can influence the pathophysiology of the disease, to change the age at onset but not to
worsen the progression thereafter. Our studies of pathological correlations suggest that the major influence of APOE
t 4 is on AP deposition. We detected no difference in neurofibrillary tangle number according to genotype if duration of
illness was covaried. This is concordant with our previous
+
observations that amyloid burden does not correlate with
severity or duration of illness [7,81, but neurofibrillary tangle
number does parallel severity of disease [8]. These clinicalpathological correlations may help generate and test hypotheses about the pathophysiologic basis of APOE genotype’s influence in Alzheimer‘s disease.
NeuroL
o
a Service
Massachusetts General Hospital
Boston, MA 02114
References
1 . Frisoni G, Bianchetti A, Govoni S,Trabucchi M. Clinical Correlates of Apolipoprotein E in Alzheimer’s Disease. Ann Neurol
1996;40:688-689 (Letter)
2. Gomez-Isla T, West H, Rebeck G, et al. Clinical and pathological correlates of apolipoprotein E e4 in Alzheimer’s disease. Ann
Neurol 1996;39:62-70
3. Locasio J , Growdon J, Corkin S. Cognitive test performance in
detecting, staging, and tracking Alzheimer’s disease. Arch Neurol
1995f2: 1087-1099
4. Growdon J H , Locascio JJ, Corkin S, et al. Apolipoprotein E
genotype does not influence rates of cognitive decline in Alzheimer‘s disease. Neurology. 1996;47:444-448
5. Dal Forno G, Rasrnusson X, Brandt J , et al. Apolipoprotein E
genotype and rate of decline in probable Alzheimer’s disease.
Arch Neurol 1996;53:345-350
6. Waring SC, Rocca WA, Smith GE, et al. Apolipoprotein E and
rate of clinical progression in Alzheimer’s disease. Neurology
1996;46:A348 (Abstract)
7. Hyman BT, Marzloff K, Arriagada PV. The lack of accumulation of senile plaques or ainyloid burden in Alzheimer’s disease
suggests a dynamic balance between amyloid deposition and resolution. J Neuropathol Exp Neurol 1993;52:594-600
8. Arriagada PV, Growdon J H , Hedley-Whyte ET, Hyman BT.
Neurofibrillary tangles but not senile plaques parallel duration
and severity of Alzheimer’s disease. Neurology 1992;42:631639
CNS Distribution of Free-Radical Inactivating
Enzymes in Amyotrophic Lateral Sclerosis
J. D. Mitchell, P. S. Fitzmaurice, J. M. Knight,
and I. C. Shaw
We read with interest the report of Przedborski and colleagues [l] and feel their work emphasizes the importance
of specifying the exact nature of the tissue used to make such
measurements and ensuring that this material is as representative of the pathological process as possible. Further insights
into discrepancies between the results of other workers in
this important area might be gained from consideration of
these issues.
Przedborski and colleagues [ 11 refer to the lack of evidence
of reduced central nervous system (CNS) selenium levels in
amyotrophic lateral sclerosis (ALS). The evidence is indeed
otherwise. The finding of increased levels of selenium and
manganese [2] in spinal cord from patients who had died of
ALS leads to early suggestions that free radical mechanisms
were important in ALS pathogenesis [3]. Most of this work
was done on whole cord sections. Increased spinal cord selenium levels have also been subsequently reported using material obtained from the lumbar enlargement, presumably us-
Annals of Neurology
Vol 40
No 4
October 1996 689
ing whole cord sections. This is also the only report so far
of increased spinal cord glutathione peroxidase (GSHPX) activities [4].The first inkling that CNS GSHPX might be
reduced in ALS came from pilot measurements on whole cord
sections obtained at three cord levels, which also tended to
suggest that activities might be higher in white than in gray
matter [ 5 ] . We have recently reported [6] on the regional
distribution of superoxide dismutase (SOD) and GSHPX in
spinal cord anterior horn tissue. W e found no detectable
GSHPX activity in anterior horn tissue from patients who
had died of ALS or reference subjects who had died of nondegenerative neurological disease. Przedborski and colleagues
[I] describe differences in GSHPX activity at different brain
sites: we have found apparent differences in S O D activities
at different cord levels.
We feel that the regionally oriented approach of Przedborski and colleagues [ l ] is vital. Further studies must take account of the possibility of variation of free-radical inactivating enzyme activities at different CNS sites as well as
significant differences in ALS patients. Measurements should
be undertaken on material that is as representative of the
motor neuron as possible to avoid possible confounding influences from non-motor neuronal tissue such as glia. It is
only by using approaches such as these that current apparent
inconsistencies in this important area will be clarified. We
might then begin to be sure that observed differences are
related to pathology and not epiphenomena or physiological
topographical variation.
Department of Neurology
Royal Preston Hospital
Sharoe Green Lane
Fulwood, Preston, PR2 9HT, UK and
Centre for Toxicology
University of Central Lancashzre
Preston, UK
Department of Neurology
Columbia University
New York, NY 10032
References
1. Prxdborski S, Donaldson D, Jakowec M, et al. Brain superoxide
dismutase, catalase, and glutathione peroxidase activities in
amyotrophic lateral sclerosis. Ann Neurol 1996;39:158-165
2. Mitchell JD, East BW. Harris IA, et al. Manganese, selenium
and other trace elements in spinal cord liver and bone in motor
neutone disease. Eur Neurol 1991;31:7-11
3. Mitchell JD, Jackson MJ, Pentland R. Indices of free radical
activity in the cerebrospinal fluid in motor neurone disease. J
Neurol Neurosurg Psychiatry 1987;50:919-922
4. Ince PG, Shaw PJ, Candy JM, et al. Iron, selenium and glutathione peroxidase activity are elevated in sporadiac motor neuron
disease. Neurosci Lett 1994;182:87-90
5. Mitchell JD, Jackson MJ. Frec radicals, amyotrophic lateral sclerosis and neurodegenerative disease. In: Smith RA, ed, Handbook of ALS. New York: Marcel Dekker, 1992;533-541
6. Shaw IC, Fitzmaurice PS, Mitchell JD, er al. Studies on cellular
free radial protection mechanisms in the anterior horn from patients with amyotrophic lateral sclerosis. Neurodegeneration
1995;4:391-396
Reply
S. Przedborski and D. Donaldson
We thank Dr Mitchell and collaborators for their interest in
our study and are grateful for their insightful comments. T o
690 Annals of Neurology Vol 40
date, there are, indeed, several pieces of evidence supporting
the implication of free radicals in amyotrophic lateral sclerosis (ALS). Aside from the different studies performed by Dr
Mitchell's group (summarized in their letter and in our article), which indisputably had and still are playing a determining role in the oxidative stress hypothesis of ALS, we should
also point out recent studies of Wiedau-Pazos and co-workers [I] about the peroxidative activity of the mutated Cul
Zn superoxide dismutase enzyme, and of Gurney and associates [2] about the benefit of vitamin E in transgenic mice
carrying familial ALS-linked mutations. W e also fully agree
that even though several studies have reported evidence that
can be interpreted as supportive of the free radical hypothesis, many investigators in the field are still looking to understand the reasons for several discrepancies among the findings. As we argued in our report, and in agreement with
Mitchell and collaborators, we have to keep in mind that
many of these free radical-scavenging enzymes have an uneven distribution within the nervous system and can show
adaptive changes. Moreover, it is generally the case that the
dying cells are only a subset of the total number of cells
present in the studied area. These issues make it very difficult
to be absolutely certain whether reported changes are primary
or secondary to the neurodegenerative disorder and whether
it is a reflection of the specific set of cells affected by the
disease or not. In any event, although some gray area remains
about the actual meaning of all of these changes (ie, magnitude, direction, relation to the neurodegenerative process,
and so on), they consistently point toward free radicals, and
thus warrant intense and additional investigation dealing
with this question.
No 4
October 1996
References
1. Wiedau-pazosM,
JJ, Rabizadeh s, er
reactiviry
of superoxide dismutase in familial amyotrophic lateral sclerosis.
Science 1996;271:515-518
Benefit of vitamin E,
2, Gurney ME,
FB, Zhaj p, et
riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol 1996;39:147-157
Corrections
In the article entitled "A P-Subunit Mutation in the Acetylcholine Receptor Channel Gate Causes Severe Slow-Channel
Syndrome" by Gomez and colleagues (Ann Neurol 1996;
39:712-723), the amino acid position bearing the mutation
should read L2"M, not L2"M. This error does not change
the interpretation of the data or the figures.
In the same article, D r Alan Pestronks name was inadvertently omitted from the authorship list. The correct authorship should be: Christopher M. Gomez, MD, PhD, Ricardo
Maselli, MD, Jason Gammack, BS, lose Lasalde, PhD, Shiori
Tamamizu, PhD, David R. Cornblath, MD, Alan Pestronk,
MD, Mohamed Lehar, MD, Mark McNamee, PhD, and
Ralph W . Kuncl, M D , PhD.
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