CNS distribution of free-radical inactivating enzymes in amyotrophic lateral sclerosis.код для вставкиСкачать
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 .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  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  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 . 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  in spinal cord from patients who had died of ALS leads to early suggestions that free radical mechanisms were important in ALS pathogenesis . 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 .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  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  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.