- Email: [email protected]
Structural and functional neuroimaging in Alzheimer's disease
396
DE L E O N A N D G E O R G E
31. Pearlson, G. D. and L. E. Tune. Cerebrospinal fluid acetylcholinesterase and cerebral atrophy in Alzheimer dementia. Soc Neurosci Abstr 14: 725, 1985. 32. Potter, P. E., J. L. Meek and N. H. Neff. Acetylcholine and choline in neuronal tissue measured by HPLC with electrochemical detection. J Neurochem 41: 188-194, 1983. 33. Rand, J. B. and C. D. Johnson. A single-vial biphasic liquid extraction assay for choline acetyltransferase using ['~H]choline. Anal Biochem !16: 361-371, 1981. 34. Rimon, R., P. Puhakka, E. Venolainen and A. J. Mandel. Choline acetyltransferase in human CSF. Psychiatr Fennica 3: 265-267, 1973. 35. Scarsella, G., G. Toshchi, S. R. Bareggi and E. Giacobini. Molecular forms of cholinestereases in cerebrospinal fluid, blood plasma, and brain tissue of the beagle dog. J Neurosci Res 4: 1%24, 1979. 36. Schain, R. J. Neurohumors and other pharmacologically active substances in cerebrospinal fluid: a review of the literature. Yale J Biol Med 33: 15-36, 1960. 37. Soininen, H., T. Halonen and P. J. Riekkinen. Acetylcholinesterase activities in cerebrospinal fluid of patients with senile dementia of Alzheimer type. Acta Neurol Stand 64: 217-224. 1981.
38. Szweda, L. I., D. D. Bloom, J. L. Dahl, M. E. Salinsky and C. D. Johnson. Choline acetyltransferase in human cerebrospinal fluid: fact or artifact? Soc Neurosci Abstr 14: 729. 1985. 39. Thai, L. J. Changes in cerebrospinal fluid associated with dementia. Ann NY Acad Sci 444: 235-241, 1985. 40. Tower, D. B. and D. McEachern. Acetylcholine and neuronal activity. I. Cholinesterase patterns and acetylcholine in the cerebrospinal fluids of patients with craniocerebral trauma. Can ,I Res 27: 105-119, 1949. 41. Tune, L., S. Gucker, M. Folstein, L. Oshida and J. T. Coyle. Cerebrospinal fluid acetylcholinesterase activity in senile dementia of the Alzheimer type. Ann Neurol 17: 46-48. 1985. 42. Welch, M. J., C. H. Markham and D. J. Jenden. Acetylcholine and choline in cerebrospinal fluid of patients with Parkinson's disease and Hungtington's chorea. ,I Neurol N~'ttrosttrL, Psychiatry 39: 367-374, 1976. 43. Wood, P. L., P. Etienne, S. Lal, S. Gauthier, S. Cajal and N. P. V. Nair. Reduced lumbar CSF somatostatin levels in Alzheimer disease. Lif~" Sci 31: 2073-2079. 1982.
Structural and Functional Neuroimaging in Alzheimer's Disease MONY
J. DE L E O N * A N D A J A X E. G E O R G E +
* D e p a r t m e n t o f Psychiatry. a n d ? D e p a r t m e n t o f R a d i o l o g y ( N e u r o r a d i o l o g y ) N Y U M e d i c a l Center, N e w York, N Y 10016
The evolution of neuroimaging technics has improved our understanding of both gross structural and physiological alterations associated with normal aging and with AIzheimer's disease. We share the optimistic view that neuroimaging will contribute to the development of antemortem markers for AD. Current CT and MRI technics allow for direct parenchymal sampling in addition to quantitating CSF distributions. Such studies followed to postmortem will yield the evidence regarding the diagnostic utility of the imaged parenchymal changes. Metabolic neuroimaging using PET and tracers for glycolytic metabolism have already contributed to our understanding of the pathophysiology of AD and its relationship to clinical symptoms. We can look forward to further advances with specific tracers for brain receptor populations and other metabolic pathways.
T H E review by Hollander and colleagues appropriately identifies many of the issues that must be considered in interpreting neuroimaging studies of normal and pathological aging. Their excellent r e v i e w of the c o m p u t e d tomography (CT) literature correctly details the history of the search for positive (inclusion) criteria for the diagnosis of A l z h e i m e r disease (AD). With consideration of their cautions, we would like to point out our enthusiasm for continued study on a n u m b e r of C T frontiers. Our understandings regarding the etiology of dilated sulci and ventricles and their implications regarding parenchymal changes in A D need to be improved. This can only be accomplished in the light of longitudinal follow-ups and p o s t m o r t e m studies. With o v e r a decade of e x p e r i e n c e using CT, many opportunities are now arising with well documented cases coming to p o s t m o r t e m examination. The search for a n t e m o r t e m CT markers for AD, we believe,
would be facilitated were national neuroimage banking centers established combining the concepts of the A l z h e i m e r ' s Disease Center and a brain bank. With the evolution of CT instrumentation, there has been in recent years a definite i m p r o v e m e n t in spatial resolution and tissue contrast sensitivity. Such i m p r o v e m e n t s have added in many cases visual e v i d e n c e of parenchymal changes in AD. Using current generation CT scanning equipment, we have found e v i d e n c e for the reduced discrimination of grey from white matter in A D [10]. It has b e c o m e c o m m o n p l a c e to see hypodensities in the periventricular white matter and lacunar infarcts in the basal ganglia and thalami [11]. Clinical use of magnetic resonance imaging (MRI) contributes to anatomical exploration for these lesions. As many as one-third o f clinically diagnosed A D patients show white matter lesions using CT. Postmortem examination has revealed that these lesions are on a microvascular basis repre-
COMMENTARY
397
senting foci of arteriolar hyalinosis with demyelination of the white matter [1,11]. Given the high frequency of these findings in age-matched normals (20%), it is probable that these changes are age, rather than specifically AD, dependent. However, the increased frequency of these parenchymal changes in AD suggests that they are contributing to the dementia process and thereby identifies a potential subgroup of patients for treatment considerations. The results from positron emission tomography (PET) studies of AD as described by Hollander et al. requires a brief comment. We agree that PET deoxyglucose and oxygen15 studies have helped to reveal the complexity of normal aging and the pathophysiology o f AD. However, PET studies using 18-F-deoxyglucose have not consistently found reductions in metabolism with increasing age in normals. In fact, only the one study cited by Hollander et al. found such evidence and the effect was small [14]. Several other groups have not found evidence for an age-dependent effect [5, 12, 15]. This is indeed a curious observation given the fairly consistent cerebral blood flow (xenon technique) evidence for age-dependent reductions, and the CT evidence for marked age-dependent structural changes. These data suggest that for the cerebral blood flow there exists a margin of safety maintaining the normal resting glucose metabolism. Thus the aging brain may in fact show some uncoupling between flow and metabolism in the absence of overt ischemia. The normal aging brain is an area of high-lighted interest given anticipated population changes worldwide and the common memory complaints heard from this group. While we are hopeful that neuroimaging will yield clinical antemortem markers for AD, we feel the PET parietal changes reported as diagnostic are interesting and should be placed into perspective. Several studies of AD have revealed that the greatest changes from normal took place in temporal and parietal areas [2-4]. In other words, these studies have identified multiple areas of reduced glucose utilization with somewhat greater reductions being found in temporal and parietal areas. One group in a series of reports using ratio analysis of PET images reported that frontoparietal ratios accurately identified all 17 AD patients relative to 7 control [9] and 2 hydrocephalus patients [13]. These reports describe a relative preservation of the frontal lobe along with focal parietal lobe changes in AD. We found using PET the relative preservation of the frontal lobe is an early feature of AD [4]. Such findings would seemingly argue for the parietal measurement as
an early marker and therefore most useful. However, our unpublished data indicates that frontoparietal ratio correctly identities only 75% of patients and controls. In our opinion, the best discriminants between AD and normal entail the use of several PET brain areas including the inferior temporal gyrus and the posterior cingulate gyrus. Furthermore, the statistics are optimized when both PET and CT are combined. Under these more complex circumstances our data approaches the correct classification of all AD patients and controls. We would in general like to caution that it remains unknown from most published studies, how many of the patients demonstrated periventricular white matter CT or MRI lesions. The lesions have been demonstrated as producing imaged metabolic asymmetrics and are often found in the parietal areas under discussion [6]. It also remains somewhat unclear what the anatomical reference was for the periventricular parenchymal PET samples, and what the effects of a large ventricle are on sampled adjacent tissue. The ventricle is relatively free of any radioactivity and a large ventricle may have the effect of reducing the measured counts from adjacent brain. This artifact may have a regional component affecting smaller tissue volumes more than larger volumes and thereby, the posterior more than the anterior samples. F o r the most part only crude mapping of the PET has been reported and unfortunately, the medial temporal lobe is among those regions not easily sampled accurately with PET. As a result areas such as the hippocampus and amygdala remain unstudied. These areas would be potentially early markers for AD pathology. In conclusion, we share in the excitement that neuroimaging of AD has presented. We concur with the authors on the importance of longitudinal study and the in vivo mapping of the brain's structure and chemistry. CT and especially MRI continue to reveal new structural defects in aging and AD and now for the first time afford the opportunity to study the parenchyma directly rather than through indirect estimates of CSF accumulations. PET which began with resting 18-F-deoxyglucose and oxygen-15 investigations currently allows study of dopamine and opiate receptors with cholinergic system markers on the horizon. Further, many current protocols now entail drug or behavioral challenges to perturb the brain to potentially reveal its biochemical secrets. Such studies will improve our understanding of both the normal and the abnormal aging of the brain and potentially lead to antemortem markers for age related diseases.
REFERENCES
1. Brun, A. and E. England. A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol 19: 253-262, 1986. 2. Chase, T. N., N. L. Foster, P. Fedio, R. Brooks, L. Mansi and G. DiChiro. Regional cortical dysfunction in AIzheimer's disease as determined by positron emission tomography. Ann Neurol 15: (Suppl) S170-S174, 1984. 3. Cutler, N. R., J. V. Haxby, R. Duara, C. L. Grady, A. D. Kay, R. M. Kessler, M. Sundaram and S. I. Rapoport. Clinical history, brain metabolism, and neuropsychological function in Alzheimer's disease. Ann Neurol 18: 298-309, 1985. 4. de Leon, M. J., S. H. Ferris, A. E. George, D. R. Christman, J. S. Fowler, C. Gentes, B. Reisberg, B. Gee, M. Emmerich, Y. Yonekura, J. Brodie, I. I. Kricheff and A. P. Wolf. Positron emission tomographic studies of aging and Alzheimer disease. Am J Neuroradiol 4: 568-571, 1983.
5. de Leon, M. J., A. E. George, S. H. Ferris, D. R. Christman, J. S. Fowler, C. I. Gentes, J. Brodie, B. Reisberg and A. P. Wolf. Positron emission tomography and computed tomography assessments of the aging human brain. J Comput Assist Tomogr 8: 88-94, 1984. 6. de Leon, M. J., A. E. George, S. H. Ferris, J. D. Miller, J. Fowler and A. P. Wolf. CT and PET study of leuckoencephalopathy in AIzheimer's disease. In: Biological Psychiatry 1985. edited by C. Chagrass, R. C. Josiassen, W. H. Bridger, K. J. Weiss, B. Stoff and G. M. Simpson. New York: Elsevier Science Publ., 1986, pp. 1316-1318. 7. Ferris, S. H., M. J. de Leon, A. P. Wolf, T. Farkas, D. R. Christman, B. Reisberg, J. S. Fowler, R. Mac Gregor, A. Goldman, A. E. George and S. Rampal. Positron emission tomography in the study of aging and senile dementia. Neurobiol Aging 1: 127-131, 1980.
398
RAPOPORT, ATACK, MAY AND GRADY
8. Frackowiak, R. S. H., C. Pozzilli, N. J. Legg, G. H. DuBoulay, J. Marshal, G. L. Lenzi and T. Jones. Regional cerebral oxygen supply and utilization in dementia--a clinical and physiological study with oxygen-15 and positron tomography. Brain 104: 753-778, 1981. 9. Friedland, R. P., T. F. Budinger, E. Koss and B. A. Ober. Alzheimer's disease: anterior-posterior and lateral hemispheric alterations in cortical glucose utilization. Neurosci Lett 53: 235-240, 1985. 10. George, A. E., M. J. de Leon, S. H. Ferris and 1. 1. Kricheff. Parenchymal CT correlates of senile dementia: loss of greywhite discriminability. Am J Neuroradiol 2: 205-213, 1981. 1981. 11. George, A. E., M. J. de Leon, C. I. Gentes, J. Miller, E. London, G. N. Budzilovich, S. Ferris and N. Chase. Leukoencephalopathy in normal and pathologic aging: 1. CT of brain lucencies. Am ,I Neuroradiol 7: 561-566, 1986.
12. Hawkins, R. A.,J. C. Mazziotta, M. E. Phelps, S.-C. Huang, D. E. Kuhl, R. E. Carson, R. J. Metter and W. H. Riege. Cerebral glucose metabolism as a function of age in man: influence of the rate constants in the fluoroxyglucose methoff..l ('creh Blood Flow Metab 3: 250--253, 1983. 13. Jagust, W. J., R. P. Friedland and T. F. Budinger. Positron emission tomography with (18F) fluorodeoxyglucose differentiates normal pressure hydrocephalus from Alzheimer-type dementia. ,I Neurol Neurosurg, Psychiatry 48: 1091-1096, 1985. 14. Kuhl, D. E., E. J. Metter, W. H. Riege and M. E. Phelps. Effects of human aging on patterns of local cerebral glucose utilization determined by the (18F) fluorodeoxyglucose method. ,I Cereb Blood Flow Metab 2: 163-171, 1982. 15. Rapoport, S. E., R. Duara, E. D. London, R. A. Margolin, M. Schwartz, N. R. Cutler, M. Partanen and N. L. Shinowara. Glucose metabolism of the aging nervous system. In: Aging, vol 22, Aging of the Brain, edited by D. Samuel, S. Algeri, S. Gershon, V. E. Grimm and G. Toffano. New York: Raven Press, 1983, pp. 111-121.
Commentary on Antemortem Markers of Alzheimer's Disease S T A N L E Y I. R A P O P O R T , J J O H N R. A T A C K C O N R A D M A Y A N D C H E R Y L L. G R A D Y L a b o r a t o r y o f N e u r o s c i e n c e s , N a t i o n a l I n st i t u t e on A g i n g N a t i o n a l I n s t i t u t e s o f H e a l t h , B e t h e s d a , M D 20892
Longitudinal studies of lateral ventricular volume using quantitative computer assisted tomography, combined with studies of cerebral metabolism and of cognitive dysfunction using positron emission tomography and neuropsychological tests. constitute a battery of markers that describe Alzheimer's disease in relation to severity.
H O L L A N D E R et al. [19] provide a comprehensive summary of the literature on markers for Alzheimer's disease (AD). The profusion of claims, however, suggests that no single marker now distinguishes AD patients or individuals at risk for AD, from healthy controls or from patients with other neurological diseases, but that a battery of markers best characterizes the disease process. In searching for a marker, it is useful to first consider the possible causes of AD. If genetic in origin, then the marker wilt be an altered expression of a gene product or an atypical DNA fragment (restriction fragment polymorphism). If caused by an infectious or toxic agent, the marker will be the agent or a product of infection or toxicity. The marker also could reflect the severity of the pathologic process irrespective of cause, e.g., a reduction of brain metabolism or brain atrophy. Identification of a specific antemortem marker for AD, having minimal overlap with healthy control or other disease groups, has been difficult because: (1) the diagnosis of AD in life is not 100% accurate, leading to heterogeneity of the AD sample; (2) a marker might be present in a control subject
who has the trait for AD but has not yet developed AD, leading to heterogeneity of the control sample; (3) if the marker is related to severity of dementia, then it may not distinguish mildly demented AD patients from controls; (4) if, like diabetes mellitus [29], AD is transmitted by polygenetic inheritance [28], more than one marker will characterize groups of patients with AD, even after the diagnosis has been ascertained by biopsy or post-mortem neuropathology 127]. Hollander et al. state that "biological markers attempt to differentiate AD patients from normal controls. Although not clinically useful, research strategies necessitate this first step." The first step frequently has been disregarded. The weakening of health screening criteria in choosing controls increases their heterogeneity and the probability of overlap with AD patients for a given marker. For example, Hollander et al. cite two publications [22,24] which indicate that cerebral metabolism declines with age. However, in studies with careful health screening by other laboratories and ours, resting cerebral metabolism has been found to be age invariant [5, 8, 9, 11, 13]. Thus~ reduced cerebral metabolism
*Requests for reprints should be addressed to Stanley I. Rapoport, M.D., Laboratory of Neurosciences, Bldg. 10. Rm 6C103. National Institute on Aging, NIH, Bethesda, MD 20892.
DE L E O N A N D G E O R G E
31. Pearlson, G. D. and L. E. Tune. Cerebrospinal fluid acetylcholinesterase and cerebral atrophy in Alzheimer dementia. Soc Neurosci Abstr 14: 725, 1985. 32. Potter, P. E., J. L. Meek and N. H. Neff. Acetylcholine and choline in neuronal tissue measured by HPLC with electrochemical detection. J Neurochem 41: 188-194, 1983. 33. Rand, J. B. and C. D. Johnson. A single-vial biphasic liquid extraction assay for choline acetyltransferase using ['~H]choline. Anal Biochem !16: 361-371, 1981. 34. Rimon, R., P. Puhakka, E. Venolainen and A. J. Mandel. Choline acetyltransferase in human CSF. Psychiatr Fennica 3: 265-267, 1973. 35. Scarsella, G., G. Toshchi, S. R. Bareggi and E. Giacobini. Molecular forms of cholinestereases in cerebrospinal fluid, blood plasma, and brain tissue of the beagle dog. J Neurosci Res 4: 1%24, 1979. 36. Schain, R. J. Neurohumors and other pharmacologically active substances in cerebrospinal fluid: a review of the literature. Yale J Biol Med 33: 15-36, 1960. 37. Soininen, H., T. Halonen and P. J. Riekkinen. Acetylcholinesterase activities in cerebrospinal fluid of patients with senile dementia of Alzheimer type. Acta Neurol Stand 64: 217-224. 1981.
38. Szweda, L. I., D. D. Bloom, J. L. Dahl, M. E. Salinsky and C. D. Johnson. Choline acetyltransferase in human cerebrospinal fluid: fact or artifact? Soc Neurosci Abstr 14: 729. 1985. 39. Thai, L. J. Changes in cerebrospinal fluid associated with dementia. Ann NY Acad Sci 444: 235-241, 1985. 40. Tower, D. B. and D. McEachern. Acetylcholine and neuronal activity. I. Cholinesterase patterns and acetylcholine in the cerebrospinal fluids of patients with craniocerebral trauma. Can ,I Res 27: 105-119, 1949. 41. Tune, L., S. Gucker, M. Folstein, L. Oshida and J. T. Coyle. Cerebrospinal fluid acetylcholinesterase activity in senile dementia of the Alzheimer type. Ann Neurol 17: 46-48. 1985. 42. Welch, M. J., C. H. Markham and D. J. Jenden. Acetylcholine and choline in cerebrospinal fluid of patients with Parkinson's disease and Hungtington's chorea. ,I Neurol N~'ttrosttrL, Psychiatry 39: 367-374, 1976. 43. Wood, P. L., P. Etienne, S. Lal, S. Gauthier, S. Cajal and N. P. V. Nair. Reduced lumbar CSF somatostatin levels in Alzheimer disease. Lif~" Sci 31: 2073-2079. 1982.
Structural and Functional Neuroimaging in Alzheimer's Disease MONY
J. DE L E O N * A N D A J A X E. G E O R G E +
* D e p a r t m e n t o f Psychiatry. a n d ? D e p a r t m e n t o f R a d i o l o g y ( N e u r o r a d i o l o g y ) N Y U M e d i c a l Center, N e w York, N Y 10016
The evolution of neuroimaging technics has improved our understanding of both gross structural and physiological alterations associated with normal aging and with AIzheimer's disease. We share the optimistic view that neuroimaging will contribute to the development of antemortem markers for AD. Current CT and MRI technics allow for direct parenchymal sampling in addition to quantitating CSF distributions. Such studies followed to postmortem will yield the evidence regarding the diagnostic utility of the imaged parenchymal changes. Metabolic neuroimaging using PET and tracers for glycolytic metabolism have already contributed to our understanding of the pathophysiology of AD and its relationship to clinical symptoms. We can look forward to further advances with specific tracers for brain receptor populations and other metabolic pathways.
T H E review by Hollander and colleagues appropriately identifies many of the issues that must be considered in interpreting neuroimaging studies of normal and pathological aging. Their excellent r e v i e w of the c o m p u t e d tomography (CT) literature correctly details the history of the search for positive (inclusion) criteria for the diagnosis of A l z h e i m e r disease (AD). With consideration of their cautions, we would like to point out our enthusiasm for continued study on a n u m b e r of C T frontiers. Our understandings regarding the etiology of dilated sulci and ventricles and their implications regarding parenchymal changes in A D need to be improved. This can only be accomplished in the light of longitudinal follow-ups and p o s t m o r t e m studies. With o v e r a decade of e x p e r i e n c e using CT, many opportunities are now arising with well documented cases coming to p o s t m o r t e m examination. The search for a n t e m o r t e m CT markers for AD, we believe,
would be facilitated were national neuroimage banking centers established combining the concepts of the A l z h e i m e r ' s Disease Center and a brain bank. With the evolution of CT instrumentation, there has been in recent years a definite i m p r o v e m e n t in spatial resolution and tissue contrast sensitivity. Such i m p r o v e m e n t s have added in many cases visual e v i d e n c e of parenchymal changes in AD. Using current generation CT scanning equipment, we have found e v i d e n c e for the reduced discrimination of grey from white matter in A D [10]. It has b e c o m e c o m m o n p l a c e to see hypodensities in the periventricular white matter and lacunar infarcts in the basal ganglia and thalami [11]. Clinical use of magnetic resonance imaging (MRI) contributes to anatomical exploration for these lesions. As many as one-third o f clinically diagnosed A D patients show white matter lesions using CT. Postmortem examination has revealed that these lesions are on a microvascular basis repre-
COMMENTARY
397
senting foci of arteriolar hyalinosis with demyelination of the white matter [1,11]. Given the high frequency of these findings in age-matched normals (20%), it is probable that these changes are age, rather than specifically AD, dependent. However, the increased frequency of these parenchymal changes in AD suggests that they are contributing to the dementia process and thereby identifies a potential subgroup of patients for treatment considerations. The results from positron emission tomography (PET) studies of AD as described by Hollander et al. requires a brief comment. We agree that PET deoxyglucose and oxygen15 studies have helped to reveal the complexity of normal aging and the pathophysiology o f AD. However, PET studies using 18-F-deoxyglucose have not consistently found reductions in metabolism with increasing age in normals. In fact, only the one study cited by Hollander et al. found such evidence and the effect was small [14]. Several other groups have not found evidence for an age-dependent effect [5, 12, 15]. This is indeed a curious observation given the fairly consistent cerebral blood flow (xenon technique) evidence for age-dependent reductions, and the CT evidence for marked age-dependent structural changes. These data suggest that for the cerebral blood flow there exists a margin of safety maintaining the normal resting glucose metabolism. Thus the aging brain may in fact show some uncoupling between flow and metabolism in the absence of overt ischemia. The normal aging brain is an area of high-lighted interest given anticipated population changes worldwide and the common memory complaints heard from this group. While we are hopeful that neuroimaging will yield clinical antemortem markers for AD, we feel the PET parietal changes reported as diagnostic are interesting and should be placed into perspective. Several studies of AD have revealed that the greatest changes from normal took place in temporal and parietal areas [2-4]. In other words, these studies have identified multiple areas of reduced glucose utilization with somewhat greater reductions being found in temporal and parietal areas. One group in a series of reports using ratio analysis of PET images reported that frontoparietal ratios accurately identified all 17 AD patients relative to 7 control [9] and 2 hydrocephalus patients [13]. These reports describe a relative preservation of the frontal lobe along with focal parietal lobe changes in AD. We found using PET the relative preservation of the frontal lobe is an early feature of AD [4]. Such findings would seemingly argue for the parietal measurement as
an early marker and therefore most useful. However, our unpublished data indicates that frontoparietal ratio correctly identities only 75% of patients and controls. In our opinion, the best discriminants between AD and normal entail the use of several PET brain areas including the inferior temporal gyrus and the posterior cingulate gyrus. Furthermore, the statistics are optimized when both PET and CT are combined. Under these more complex circumstances our data approaches the correct classification of all AD patients and controls. We would in general like to caution that it remains unknown from most published studies, how many of the patients demonstrated periventricular white matter CT or MRI lesions. The lesions have been demonstrated as producing imaged metabolic asymmetrics and are often found in the parietal areas under discussion [6]. It also remains somewhat unclear what the anatomical reference was for the periventricular parenchymal PET samples, and what the effects of a large ventricle are on sampled adjacent tissue. The ventricle is relatively free of any radioactivity and a large ventricle may have the effect of reducing the measured counts from adjacent brain. This artifact may have a regional component affecting smaller tissue volumes more than larger volumes and thereby, the posterior more than the anterior samples. F o r the most part only crude mapping of the PET has been reported and unfortunately, the medial temporal lobe is among those regions not easily sampled accurately with PET. As a result areas such as the hippocampus and amygdala remain unstudied. These areas would be potentially early markers for AD pathology. In conclusion, we share in the excitement that neuroimaging of AD has presented. We concur with the authors on the importance of longitudinal study and the in vivo mapping of the brain's structure and chemistry. CT and especially MRI continue to reveal new structural defects in aging and AD and now for the first time afford the opportunity to study the parenchyma directly rather than through indirect estimates of CSF accumulations. PET which began with resting 18-F-deoxyglucose and oxygen-15 investigations currently allows study of dopamine and opiate receptors with cholinergic system markers on the horizon. Further, many current protocols now entail drug or behavioral challenges to perturb the brain to potentially reveal its biochemical secrets. Such studies will improve our understanding of both the normal and the abnormal aging of the brain and potentially lead to antemortem markers for age related diseases.
REFERENCES
1. Brun, A. and E. England. A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol 19: 253-262, 1986. 2. Chase, T. N., N. L. Foster, P. Fedio, R. Brooks, L. Mansi and G. DiChiro. Regional cortical dysfunction in AIzheimer's disease as determined by positron emission tomography. Ann Neurol 15: (Suppl) S170-S174, 1984. 3. Cutler, N. R., J. V. Haxby, R. Duara, C. L. Grady, A. D. Kay, R. M. Kessler, M. Sundaram and S. I. Rapoport. Clinical history, brain metabolism, and neuropsychological function in Alzheimer's disease. Ann Neurol 18: 298-309, 1985. 4. de Leon, M. J., S. H. Ferris, A. E. George, D. R. Christman, J. S. Fowler, C. Gentes, B. Reisberg, B. Gee, M. Emmerich, Y. Yonekura, J. Brodie, I. I. Kricheff and A. P. Wolf. Positron emission tomographic studies of aging and Alzheimer disease. Am J Neuroradiol 4: 568-571, 1983.
5. de Leon, M. J., A. E. George, S. H. Ferris, D. R. Christman, J. S. Fowler, C. I. Gentes, J. Brodie, B. Reisberg and A. P. Wolf. Positron emission tomography and computed tomography assessments of the aging human brain. J Comput Assist Tomogr 8: 88-94, 1984. 6. de Leon, M. J., A. E. George, S. H. Ferris, J. D. Miller, J. Fowler and A. P. Wolf. CT and PET study of leuckoencephalopathy in AIzheimer's disease. In: Biological Psychiatry 1985. edited by C. Chagrass, R. C. Josiassen, W. H. Bridger, K. J. Weiss, B. Stoff and G. M. Simpson. New York: Elsevier Science Publ., 1986, pp. 1316-1318. 7. Ferris, S. H., M. J. de Leon, A. P. Wolf, T. Farkas, D. R. Christman, B. Reisberg, J. S. Fowler, R. Mac Gregor, A. Goldman, A. E. George and S. Rampal. Positron emission tomography in the study of aging and senile dementia. Neurobiol Aging 1: 127-131, 1980.
398
RAPOPORT, ATACK, MAY AND GRADY
8. Frackowiak, R. S. H., C. Pozzilli, N. J. Legg, G. H. DuBoulay, J. Marshal, G. L. Lenzi and T. Jones. Regional cerebral oxygen supply and utilization in dementia--a clinical and physiological study with oxygen-15 and positron tomography. Brain 104: 753-778, 1981. 9. Friedland, R. P., T. F. Budinger, E. Koss and B. A. Ober. Alzheimer's disease: anterior-posterior and lateral hemispheric alterations in cortical glucose utilization. Neurosci Lett 53: 235-240, 1985. 10. George, A. E., M. J. de Leon, S. H. Ferris and 1. 1. Kricheff. Parenchymal CT correlates of senile dementia: loss of greywhite discriminability. Am J Neuroradiol 2: 205-213, 1981. 1981. 11. George, A. E., M. J. de Leon, C. I. Gentes, J. Miller, E. London, G. N. Budzilovich, S. Ferris and N. Chase. Leukoencephalopathy in normal and pathologic aging: 1. CT of brain lucencies. Am ,I Neuroradiol 7: 561-566, 1986.
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Commentary on Antemortem Markers of Alzheimer's Disease S T A N L E Y I. R A P O P O R T , J J O H N R. A T A C K C O N R A D M A Y A N D C H E R Y L L. G R A D Y L a b o r a t o r y o f N e u r o s c i e n c e s , N a t i o n a l I n st i t u t e on A g i n g N a t i o n a l I n s t i t u t e s o f H e a l t h , B e t h e s d a , M D 20892
Longitudinal studies of lateral ventricular volume using quantitative computer assisted tomography, combined with studies of cerebral metabolism and of cognitive dysfunction using positron emission tomography and neuropsychological tests. constitute a battery of markers that describe Alzheimer's disease in relation to severity.
H O L L A N D E R et al. [19] provide a comprehensive summary of the literature on markers for Alzheimer's disease (AD). The profusion of claims, however, suggests that no single marker now distinguishes AD patients or individuals at risk for AD, from healthy controls or from patients with other neurological diseases, but that a battery of markers best characterizes the disease process. In searching for a marker, it is useful to first consider the possible causes of AD. If genetic in origin, then the marker wilt be an altered expression of a gene product or an atypical DNA fragment (restriction fragment polymorphism). If caused by an infectious or toxic agent, the marker will be the agent or a product of infection or toxicity. The marker also could reflect the severity of the pathologic process irrespective of cause, e.g., a reduction of brain metabolism or brain atrophy. Identification of a specific antemortem marker for AD, having minimal overlap with healthy control or other disease groups, has been difficult because: (1) the diagnosis of AD in life is not 100% accurate, leading to heterogeneity of the AD sample; (2) a marker might be present in a control subject
who has the trait for AD but has not yet developed AD, leading to heterogeneity of the control sample; (3) if the marker is related to severity of dementia, then it may not distinguish mildly demented AD patients from controls; (4) if, like diabetes mellitus [29], AD is transmitted by polygenetic inheritance [28], more than one marker will characterize groups of patients with AD, even after the diagnosis has been ascertained by biopsy or post-mortem neuropathology 127]. Hollander et al. state that "biological markers attempt to differentiate AD patients from normal controls. Although not clinically useful, research strategies necessitate this first step." The first step frequently has been disregarded. The weakening of health screening criteria in choosing controls increases their heterogeneity and the probability of overlap with AD patients for a given marker. For example, Hollander et al. cite two publications [22,24] which indicate that cerebral metabolism declines with age. However, in studies with careful health screening by other laboratories and ours, resting cerebral metabolism has been found to be age invariant [5, 8, 9, 11, 13]. Thus~ reduced cerebral metabolism
*Requests for reprints should be addressed to Stanley I. Rapoport, M.D., Laboratory of Neurosciences, Bldg. 10. Rm 6C103. National Institute on Aging, NIH, Bethesda, MD 20892.