REVIEW 

Annals of Nuclear Medicine Vol. 15, No. 2, 85-92, 2001 

Cerebral blood flow and metabolic abnormalities in Alzheimer's disease 

Hiroshi MATSUDA 

Department of Radiology, National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry 

In this review I summarize observations of PET and SPECT studies about cerebral blood flow and metabolic abnormalities in Alzheimer's disease. In very early AD flow or metabolism reduces first in the posterior cingulate gyrus and precuneus. This reduction may arise from functional deafferentation caused by primary neural degeneration in the remote area of the entorhinal cortex that is the first to be pathologically affected in AD. Then medial temporal structures and parietotemporal association cortex show flow or metabolic reduction as disease processes. The reason why flow or metabolism in medial temporal structures shows delay in starting to reduce in spite of the earliest pathological affection remains to be elucidated. It is likely that anterior cingulate gyrus is functionally involved, since attention is the first non-memory domain to be affected, before deficits in language and visuospatial functions. However few reports have described involvement in the anterior cingulate gyrus. Relationship between cerebral blood flow or metabolism and apolipoprotein E genotype has been investigated. Especially, the APOE 84 allele has been reported to increase risk and to lower onset age as a function of the inherited dose of the 84 allele. Reduction of flow or metabolism in the posterior cingulate gyrus and precuneus has been reported even in presymptomatic nondemented subjects who were cognitively normal and had at least a single e4 allele. On the contrary the relation of e4 allele to the progression rate of AD has been controversial from neuroimaging approaches. PET and SPECT imaging has become to be quite useful for assessing therapeutical effects of newly introduced treatment for AD. Recent investigations observed significant regional flow increase after donepezil hydrochloride treatment. Most of these observations have been made by applying computer assisted analysis of three-dimensional stereotactic surface projection or statistical parametric mapping instead of a conventional regions of interest technique. 

Key words: Alzheimer's disease, SPECT, PET, regional cerebral blood flow, regional cerebral metabolic rate for glucose 

INTRODUCTION 

FOR ALMOST TWO DECADES, PET and SPECT have been used to investigate functional alteration of the brain in patients with Alzheimer's disease (AD). Recent advances of instruments enabled us to investigate functional alteration 

Received February 19, 2001 , revision accepted February 19, 2001. 
For reprint contact: Hiroshi Matsuda, M.D., Department of Radiology, National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, 4-1-1 , Ogawahigashi, Kodaira, Tokyo 187-8551 , JAPAN. 
E-mail : matsudah@ncnpmusashi.gr.jp 

in fine structures of not only cortical but also subcortical areas with high spatial resolution. Moreover development of computer assisted analysis using three-dimensional stereotactic surface projection (3D-SSP)1-3 or statistical parametric mapping (SPM)4 afforded objective and more reliable assessment of functional abnormalities by means of stereotactic coordinates than visual interpretation of raw tomographic images. This stereotactic approach is voxel by voxel analysis in the stereotactic space to avoid subjectivity and to adopt the principle of data-driven analysis. Although alternative approach by a regions of interest (ROI) technique has gained general acceptance, it is limited by the fact that the selection of sample depends on the observer's a priori choice and hypothesis, and leaves large areas of the brain unexplored. Recent medications like cholinesterase inhibitors; e.g., tacrine hydrochloride, donepezil, and rivastigmine tartrate has turned out to be able to delay the progression of AD. 5 This fact makes present studies on AD go toward earlier diagnosis and longitudinal investigation to assess therapeutical effects. This review article summarizes cerebral blood flow and metabolic abnormalities in AD. 

FUNCTIONALLY AFFECTED AREAS IN AD 

Cerebral association cortex Many researchers have demonstrated metabolic and blood flow reductions in the parieto-temporal association cortex. 6-21 This finding has been widely recognized as a diagnostic pattern for AD. Metabolic abnormality in parietal association cortex is the best discriminator of patients with probable AD from normal subjects. 22 The parieto-temporal involvement is bilateral, although asymmetry in the degree of flow or metabolic reduction is recognized. 7,12, 13.20.23-25 While frontal association cortex is reduced in certain cases, often in advanced disease. 11,l3,21,26 Several investigators have addressed longitudinal changes of functional alteration in AD.13,27-30 It has been reported consistently that the posterior association cortex is the first cortical region to be affected in AD. This deficit then spreads to the frontal lobes as the disease progresses with persisting asymmetry. 

Medial temporal areas 

Most previous pathological and morphological studies suggest that structures within the medial temporal structures, amygdala, hippocampal formation, entorhinal cortex, and parahippocampal and fusiform gyri, are the first to be affected in AD with histological changes, including amyloid deposits and neurofibrillary changes. 31-37 This pattern is in keeping with the first neuropsychological deficit in AD being episodic memory loss. 38,39 The reduced rCBF in the medial temporal structures demonstrated by PET 40 or by a recent high-resolution SPECT system is consistent with these pathological findings. 41-43 Our longitudinal study 44 also observed significant flow reductions in the medial temporal area on the left side when the mean score of mini-mental state examination (MMSE) was 22.3. The possibility cannot be excluded that this decrease may be related to a partial volume effect from focal atrophy. However our cross-sectional study 45 on both anatomical and functional measurements in the same individuals using MRI and SPECT would explain that the rCBF reduction in the hippocampus is not solely due to a partial volume effect in AD. Early AD patients showed much less decline ( 12.4 % on the average) in rCBF than that (22.2%) in volume in the hippocampus compared with normal control, while advanced AD patients showed almost equal decline in rCBF (25.9%) and in volume (29.3%). This much greater difference in rCBF than in volume between early and advanced AD patients would be attributed not to a mere partial volume effect but to disease process. 

Our longitudinal study 44 did not observe significant decrease in hippocampal blood flow in very early AD patients with the MMSE score of above 24, either. In mild-to-moderate AD patients, Ishii et al. 46,47 demonstrated PET findings of significant reduction of oxygen metabolism in medial temporal structures without flow decrease. They suggested the presence of luxury perfusion in the medial temporal structures of AD patients. Elevation of lactate in experimentally injured hippocampi of rat 48 might support the presence of luxury perfusion. These results suggest the possibility that the lactic acidosis introduces the relative increase of rCBF in atrophic hippocampi in early AD patients. 

Posterior cingulate gyrus and precuneus 

In a very early stage of AD, even before clinical diagnosisof probable AD is possible, decrease of regional cerebral blood flow as well as glucose metabolism in the posterior cingulate gyrus and precuneus has been reported using PET 49,50 or SPECT. 44.51 3D-SSP and SPM methods have made these observations. We could hardly distinguish slight decrease of flow or metabolism in this area in patients with early AD by visual inspection, since metabolic activity or flow in the posterior cingulate gyrus is as high as primary visual cortex in normal individuals at rest. 50 Reduced PET measures of glucose metabolism in AD remain even after accounting for partial volume effects; thus, it is more than just an artifact resulting from increased cerebral fiuid space. 52   
The observation that metabolic reduction in this area predicts cognitive decline in presymptomatic persons indicates that the pathophysiologic process begins well before even mild or questionable dementia is recognized clinically.53,54 PET measures of glucose hypometabolism reflect decreased synaptic activity due either to loss or dysfunction of synapses 55 and regional metabolic deficits observed on PET may reflect projections from dysfunctional neurons in other brain lesions. In non-human pri-mates, lesions of entorhinal cortex that is the first to be affected in AD 35 cause significant and long-lasting metabolic decline in a small set of remote brain regions, especially in the inferior parietal, posterior temporal, posterior cingulate and associative occipital cortices, and posterior hippocampal regions. 56 These results suggest that flow or metabolic reduction in the posterior cingulate gyrus and precuneus indicates the earliest functional changes in AD as a remote effect. According to our longitudinal SPECT study, 44 flow decrease in the posterior cingulate gyrus and precuneus became ambiguous as disease processed. This may be due to more stability of flow in this area than that of other cortical areas as disease process. 

The area of the posterior cingulate gyrus and precuneus is known to be important in memory.57 A PET study revealed activation of the retrosplenial area of the cingulate cortex during the episodic memory encoding task.58 Clinical evidence of existence of brain tumor59 or arteriovenous malformation60 in the retrosplenial cingulate cortex supports the importance of this area in memory function. The retrosplenial cortex receives input from the subiculum and projects to the anterior thalamus, thus providing and alternative route between the hippocampus and thalamus. Medial temporal structures involved in memory receive anterior thalamic input directly via the cingulate bundle and indirectly through a relay in the retrosplenial cortex.60 This thalamocortical portion of Papez' circuit61 may be important in memory, and that lesions of the cingulum and retrosplenial cortex may cause memory dysfunction by disrupting this pathway. 

The PET study also showed activation in the precuneus during the episodic memory retrieval task but not in the control or the semantic memory tasks 57 Little is known concerning either the functions or connectivity of the precuneus. Anatomical evidence indicates prefrontal, temporal, occipital and thalamic connections to the precuneus. 

Anterior cingulate gyrus 

Current evidence suggests that after an initial amnesic stage in Alzheimer's disease, attention is the first non-memory domain to be affected, before deficits in language and visuospatial functions.62 This is consistent with the possibility that difficulties with activities of daily living, which occur in even mildly demented patients, may be related to attentional deficits. 

Following involvment of the medial temporal structures, neuropathological changes of neurofibrillary tangles spread to the basal forebrain and anterior cingulate before encroaching of the neocortical association areas.33 Decreased rCBF in the anterior cingulate gyrus has been reported in subjects with questionable AD at baseline SPECT who converted to AD on follow-up.51 Among AD patients it appears that divided attention is particularly vulnerable while sustained attention is relatively preserved in the early stage.62,63 Divided attention activates the anterior cingulate gyrus though sustained attention does not.64,65 This tendency may be peculiar to older adults comparing with younger adults.66 

Functionally preserved areas in AD 

The primary motor, sensory, and visual cortices are typi-cally spared until the very severe stages of the disease, and the subcortical structures such as thalamus also remain relatively affected. 18,20,21.44.67 The stereotactic PET and SPECT analysis revealed the strong invulnerability of pons.44,68 Cerebellar blood flow are relatively preserved in mild to moderate AD, but significantly reduced in advanced AD with distinct atrophy.69

Relationship between cerebral blood flow/metabolism and apolipoprotein E genotype 

Apolipoprotein E (APOE) is located on the arm of human chromosome 19 within an apolipoprotein gene family and has 3 common alleles, designated e2, e3, and e4.70 These genetic variations result in amino acid substitutions at positions 112 and 158 of the protein. Minor variations and different genotypes have a major effect on the risk and onset of AD.71 Especially, the APOE 84 allele has been reported to increase risk and to lower onset age as a function of the inherited dose of the 84 allele 71 These findings have been also confirmed in Japanese studies 72 A lot of studies on APOE have given a sidelight on its function, neurofibrillary tangle formation, amyloid plaque deposition or clearance, cholesterol transport, oxidation, and so on 73-75 

Reduction of flow or metabolism in the posterior cingulate gyri and precunei has been reported even in presymptomatic nondemented subjects who were cognitively normal and had at least a single e4 allele 53,54,76 The relation of e4 allele to the progression rate of AD has been controversial from the standpoint of both neuropsychological and neuroimaging approaches. Lehtovirta et al.30 reported a three-year longitudinal study in which the homozygous e4 allele patients with AD had lower cerebral perfusion at the baseline in the parietal and occipital cortices and at the follow-up in the temporal, parietal, and occipital cortices than patients with AD with one or no e4 alleles. This result agreed with the report that e4 homozygosity is associated with a faster rate of cognitive decline 77 By contrast, many investigators suggested that the presence of the e4 allele does not affect clinical progression in AD patients.78-80 Slooter et al.80 reported no significant difference in cognitive function and severity of dementia for AD patients with and without e4 allele. Cross-sectional PET studies demonstrated no distinct patterns of cerebral metabolic rate for glucose (rCMRGlu) in AD patients as a function of genotype 81,82 On the other hand, some investigators presented longer disease duration in e4 carriers than in non-carriers and suggested that e4 is associated with a less aggressive form of AD.83-85 

In subjects in nondemented relatives at risk for AD, Small et al. found that carrying the e4 allele was associated with significantly lower parietal rCMRGlu and greater parietal asymmetry.53 However, in patients with AD, van Dyck et al. found that the no-carrying the e4 allele subjects had significantly greater rCMRGlu asymmetry in superior parietal and superior temporal regions. 84 They did not make reference to consistent difference in left and right sides. Asymmetry in rCMRGlu may take place in the medial temporal structures in relation to APOE genotype. MRI studies demonstrated that smaller hippocampal volumes in e4 carriers than in non-carriers especially on the right side. 86,87 

Lehtovirta et al.30,88 reported that the e4 carriers showed more decrease in occipital rCBF in time-course changes than non-carriers. This phenomenon might be ascribed to the greater cholinergic depletion in the e4 carriers reflecting an earlier hypoperfusion in the areas where cholinergic innervation is more sparse. 88 Presence of diffuse Lewy body might also have to do with this phenomenon. The e4 allele is reported to be highly related to dlffuse Lewy body disease 89 that shows hypometabolism in occipital lobes.90 

Effects of cholinesterase inhibitor on cerebral blood flow/metabolism 

Pharmacological, biochemical, and functional imaging observations implicate a cholinergic defect underlying many behavioral abnormalities in AD. 91 Donepezil hydrochloride is a piperidine-based acetylcholinesterase inhibitor that is clinically used for the symptomatic treatment of mild to moderate AD.92,93 Donepezil has been shown to significantly improve cognition and to maintain global function compared with placebo, and also to be well tolerated. 93 The results of 24-week studies have indicated that the well-established benefits of donepezil on cognition may extend to improvement of the ability to perform complex activities of daily living. 92 Although donepezil has been approved in many countries for the treatment of patients with mild to moderate AD, its effect on cerebral blood flow or metabolism has not been fully investigated yet. 

In a longitudinal study using 99m-Tc-HMPAO SPECT with SPM analysis, Warren et al.94 found a significant flow increase in occipital lobes after donepezil treatment in a AD patient with visual form. The presence of lower lateral orbital frontal and dorsolateral frontal perfusion suggested good response to donepezil and was significantly related to behaviors of irritability, disinhibition, and eupholia. 95 Staff et al.96 also observed the most significant increase in frontal lobes as well as overall slight increase in global cerebral blood flow after donepezil treatment in AD patients. 

CONCLUSION 

PET and SPECT imaging for the assessment of cerebral blood flow and metabolism will play still more important roles in diagnosing early AD, staging of AD, and assessing therapeutical indication and its effects. Recently developed tracers for a PET study 97-99 have directly measured inhibition of cholinesterase by donepezil treatment.100 Development of a SPECT tracer for routine clinical use would expect this direct measurement. 

REFERENCES 

1. Minoshima S, Berger KL, Lee KS, Mintun MA. An automated method for rotational correction and centering of three-dimensional functional brain images. J Nucl Med 1992; 33: 1579-1585. 

2. Minoshima S, Koeppe RA, Mintun MA, et al. Automated detection of the intercommissural (AC-PC) line for stereotactic localization of functional brain images. J Nucl Med 1993; 34: 322-329. 

3. Minoshima S, Koeppe RA, Frey KA, Kuhl DE. Anatomical standardization: linear scaling and nonlinear warping of functional brain images. J Nucl Med 1993 ; 35: 1528-1537. 

4. Frith CD, Friston KJ, Ashburner J, et al. Principles and methods. In Human Brain Function, Frackowiak RS J, Fristo KJ, Frith CD, Dolan RJ, Mazziotta JC (eds), 1st ed, San Diego; Academic Press, 1997: 3-159. 

5. Emilinen G, Beyreuther K. Masters CL, Maloteaux JM, Prospects for pharmacological intervention in Alzheimer disease. Arch Neurol 2000; 57: 454-459. 

6. Friedland RP, Budinger TF, Ganz E, et al. Regional cerebral metabolic alterations in dementia of the Alzheimer type: positron emission tomography with [18-F]fluorodeoxyglucose. J Comput Assist Tomogr 198_3; 7: 590-598. 

7. Foster NL, Chase TN, Fedio P, Psztonas NJ, Brooks RA, Di Chiro G. Alzheimer's disease: focal cortical changes shown by positron emission tomography. Neurology 1983; 33: 961-965. 

8. Kuhl DE. Imaging local brain function with emission computed tomography. Radiology 1984; 150: 625-631 . 

9. Foster NL, Chase TN, Mansi L, et al. Cortical abnormalities in Alzheimer's disease. Ann Neurol 1984; 16: 649-654. 

10. Kuhl DE, Metter EJ, Riege WH. Patterns of cerebral glucose utilization in depression, multiple infarct dementia, and Alzheimer' s disease. Res Pub Assoc Res Nerv Ment Dis 1985; 63: 211-226. 

11 . Cutler NR, Haxby JV, Duara R, et al. Clinical history, brain metabolism, and neuropsychological function in Alzheimer's disease. Ann Neurol 1985; 18: 298-309. 

l2. Friedland RP, Budinger TF, Koss E, Ober BA. Alzheimer' s disease: anterior-posterior and lateral hemispheric alterations in cortical glucose utilization. Neurosci Lett 1985; 53: 235-240. 

13. Duara R, Grady C, Haxby JV, et al. PET in Alzheimer's disease. Neurology 1986; 36: 879-887. 

14. McGeer PL, Kamo H, Harrop R, et al. Positron emission tomography in patients with clinically diagnosed Alzheimer' s disease. Can Med Assoc J Neurol Neurosurg Psychiatry 1986; 134: 597-607. 

15. Polinsky RJ, Noble H, Di Chiro G, Nee LE, Feldman RG, Brown RT. Dominantly inherited Alzheimer's disease: cerebral glucose metabolism. J Neurol Neurosurg Psychiatry 1987; 50: 752-757. 

16. Johnson KA, Holman BL, Mueller SP, et al. Single photon emission computed tomography in Alzheimer's disease: abnormal iofetamine I 123 uptake reflects dementia severity. Arch Neurol 1988; 45: 392-396. 

17. Herholz K, Adams R, Kessler J, Szelies B, Grond M, HeissWD. Criteria for the diagnosis of Alzheimer's disease with PET. Dementia 1990; 1 : 156-164. 

18. Heiss WD, Szelies B, Kessler J, Herholz K. Abnormalities of energy metabolism in Alzheimer' s disease studies with PET. Ann NY Acad Sci 1991 ; 640: 65-71 . 

19. Guze BH, Hoffman JM, Baxter LR Jr, Mazziota JC, Phelps ME. Functional brain imaging and Alzheimer-type dementia. Alzheimer Dis Assoc Disord 1991 ; 5: 215-230. 

20. Nyback H, Nyman H, Blomqvist G, Sjorgren I, Stone-Elander S. Brain metabolism in Alzheimer's dementia: studies of 11C-deoxyglucose accumulation, CSF mono-amine metabolites and neuropsychological test performance in patients and healthy subjects. J Neurol Neurosurg Psychiatry 1991 ; 54: 672-678. 

21. Mielke R, Herholz K, Grond M, Kessler J, Heiss WD. Differences of regional cerebral glucose metabolism between presenile and senile dementia of Alzheimer type. Neurobiol Aging 1992; 13: 93-98. 

22. Minoshima S, Frey KA, Koeppe RA, Foster NL, Kuhl DE. A diagnostic approach in Alzhelmer's disease using three-dimensional stereotactic surface projections of fluorine- 18-FDG PET. J Nucl Med 1995; 36: 1238-1248. 

23. Cutler NR, Duara R, Creasey H, et al. NIH Conference. Brain imaging: aging and dementia. Ann Intern Med 1984; 101 : 355-369. 

24. Koss E, Friedland RP, Ober BA, Jagust WJ. Differenccs in lateral hemispheric asymmetries of glucose utilization between early- and late-onset Alzheimer-type dementia. Am J Psychiatry 1985; 142: 638-640. 

25. McGeer EG, Peppard RP. McGeer PL, et al. Fluorine-18-fluorodeoxyglucose positron emission tomography studies in presumed Alzheimer cases, including 13 serial scans. Can J Neurol Sci 1990; 17: 1-11. 

26. Kumar A, Scapiro MB, Haxby JV, Grady CL, Friedland RP. Cerebral metabolic and cognitive studies in dementia with frontal lobe behavioral features. J Psychiatr Res 1990; 24: 97- 109. 

27. Haxby JV, Grady CL, Koss E, et al. Longitudinal study of cerebral metabolic asymmetries and associated neuropsychological patterns in early dementia of the Alzheimer type. Arch Neurol 1990; 47: 753-760. 

28. Smith GS, Leon ML, George AE, et al. Topography of cross-sectional and longitudinal glucose metabolic deficits in Alzheimer's disease. Pathophysiologic implications. Arch Neurol 1992; 49: 1142-1150. 

29. Brown DRP, Hunter R, Wyper DJ, et al. Longitudinal changes in cognitive function and regional cerebral function in Alzheimer's disease: a SPECT blood flow study. J Psychiatr Res 1996; 30: 109-126. 

30. Lehtovirta M, Kuikka J, Helisalmi S, et al. Longitudinal SPECT study in Alzheimer' s disease: relation to apolipoprotein E polymorphism. J Neurol Neurosurg Psychiatry 1998; 64: 742-746. 

31. Brun A, Gustafson L. Distribution of cerebral degeneration in Alzheimer's disease. A clinico-pathological study. Arch Psychiat Nervenkr 1976; 223: 15-33. 

32. Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL. Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science 1984; 225: 1168-1170. 

33. Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathologica 1991 ; 82: 239-256. 

34. Braak H, Braak E. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging 1995; 16: 271-
284. 

35. Gomez-Isla T. Price TL, McKeel DW. Morris JC, Growdon JH, Hyman BT. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer' s disease. J Neuro-science 1996; 16: 4491-4500. 

36. Jack CR, Petersen RC, Xu YC, et al. Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's disease. Neurology 1997; 49: 786-794. 

37. Bobinski M, Leon MJ, Convit A, et al. MRI of entorhinal cortex in mild Alzheimer's disease. Lancet 1999; 353: 38-40 . 

38. Huff FJ, Becker JT, Bell SH, Nebes RD, Holland AL, Boller F. Cognitive deficits and clinical diagnosis of Alzheimer's disease. Neurology 1987; 37: 1119-1124. 

39. Welsh KA, Butters N, Hughes JP, Mohs RC, Heyman A. Detection and staging of demential in Alzheimer's disease: use of the neuropsychological measures developed for the consortium to establish a registry for Alzheimer's disease. Arch Neurol 1992; 49: 448-452. 

40. Pearlson GD, Harris GJ, Powers RE, et al. Quantitative changes in mesial temporal volume, regional cerebral blood flow, and cognition in Alzheimer's disease. Arch Gen Psychiatry 1992; 49: 402-408. 

41 . Ohnishi T, Hoshi H, Nagamachi S, et al. High-resolution SPECT to assess hippocampal perfusion in neuropsychiatric diseases. J Nucl Med 1995; 36: 1163-1169. 

42. Julin P, Lindqvist J, Svensson L, Slomka P, Wahlund LO. MRI-guided SPECT measurements of medial temporal lobe blood flow in Alzhemer's disease. J Nucl Med 1997; 38: 914-919.

43. Rodriguez G, Nobili F. Copello F, et al. 99mTC-HMPAO regional cerebral blood flow and quantitative electroencephalography in Alzheimer' s disease: a correlative study. J Nucl Med 1 999; 40: 522-529. 

44. Kogure D. Matsuda H, Ohnishi T, et al. Longitudinal evaluation of early Alzheimer's disease using brain perfusion SPECT. J Nucl Med 2000; 41 : 1155-1162. 

45. Kitayama N, Kogure D, Ohnishi T, et al. MRl-based volumetry of hippocampal gray-matter, and SPECT measurements of hippocampal blood flow for the diagnosis of Alzheimer' s disease: comparison with Statistical Parametric Mapping. Brain Science and Mental Disorders 1999; 10: 299-306. 

46. Ishii K, Kitagaki H, Kono M, Mori E. Decreased medial temporal oxygen metabolism in Alzheimer' s disease shown by PET. J Nucl Med 1996; 37: 1159-1165. 

47. Ishii K. Sasaki M, Yamaji S. Sakamoto S, Kitagaki H, Mori E. Paradoxical hippocampus perfusion in mild-to-moderate Alzheimer's disease. J Nucl Med 1998; 39: 293-298. 

48. Dhillon HS, Dose JM, Scheff SW, Prasad MR. Time course of changes in lactate and free fatty acids after experimental brain injury and relationship to morphologic damage. Exp Neurol 1997; 146: 240-249. 

49. Minoshima S, Foster NL, Kuhl DE. Posterior cingulate cortex in Alzheimer's disease. Lancet 1994; 344: 895. 

50. Minoshima S, Giordani B, Berent S, et al. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer' s disease. Ann Neurol 1997; 42: 85-94. 

51. Johnson KA, Jones BL, Holman JA, et al. Preclinical prediction of Alzheimer's disease using SPECT. Neurology 1998; 50: 1563-1571. 

52, Ibanez V, Pietrini P, Alexandar GE, et al, Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer's disease. Neurology 1998; 50: 1585-1593. 

53. Small GW, Mazziotta JC, Collins MT, et al. Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA 1995; 273: 942-947. 

54. Small GW, Ercoli LM, Silverman DH, et al. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc Natl Acad Sci USA 2000; 97: 6037-6042. 

55. Mazziota JC, Phelps ME. Principles and Applications for the Brain and Heat. In Positron Emission Tomography and Autoradiography, Phelps ME, Mazziota JC, Schelbert H (eds), New York; Raven Press, 1986: 493-579. 

56. Meguro K. Blaizot X, Kondoh Y, Le Mestric C, Baron JC, Chavoix C. Neocortical and hippocampal glucose hypometabolism following neurotoxic lesions of the entorhinal and perirhinal cortices in the non-human primate as shown by PET. Implications for Alzheimer's disease. Brain 1999; 122: 1519-1531. 

57. Desgranges B, Baron JC, de la Sayette V, et al. The neural substrates of memory systems impairment in Alzheimer's disease. A PET study of resting brain glucose utilization. Brain 1998; 121: 611-631. 

58. Fletcher PC, Frith CD, Grasby PM, Shallice T, Frackwiak RSJ, Dolan RJ. Brain system for encoding and retrieval of auditory-verbal memory. Brain 1995; 118: 401-416. 

59. Rudge P, Warrington EK. Selective impairment of memory and visual perception in splenial tumours. Brain 1991 ; 114: 349-360. 

60. Valenstein E, Bowers D. Verfaellie M, Heilman KM, Day A, Watson RT. Retrosplenial amnesia. Brain 1987; 110: 1631-1646. 

61 . Papez JW. A proposed mechanism of emotion. Arch Neurol Psychiatry 1937; 38: 725-743. 

62. Perry RJ, Hodges JR. Attention and executive deficits in Alzheimer's disease. A critical review. Brain 1999; 122:383-404. 

63. Rizzo M, Anderson SW, Dawson J, Myers R, Ball K. Visual attention impairments in Alzheimer's disease. Neurology 2000; 54: 1954-1959. 

64. Iidaka T, Anderson ND. Kapur S, Cabeza R, Craok FI. The effect of divided attention on encoding and retrieval in episodic memory revealed by positron emission tomography. J Cogn Neurosci 2000; 12: 267-280. 

65. Corbetta M, Miezin FM. Dobmeyer S, Shulman GL, Pertersen SE. Selective and divided attention during Visual Discrimination of shape, color, and speed: functional anatomy by positron emission tomography. J Neurosci 1991 ; 11 : 2383-2402. 

66. Madden DJ, Turkington TG, Provenzale JM, Hawk TC, Hoffman JM, Coleman RE. Selective and divided visual attention: Age-Related changes in regional cerebral blood flow measured by H215O PET. Hum Brain Map 1997; 5: 389-409. 

67. Benson DF, Kuhl DE, Hawkins RA, Phelps ME, Cummings JL, Tsai SY. The fluorodeoxyglucose 18F scan in Alzheimer's disease and multi-infarct dementia. Arch Neurol 1983; 40: 711-714. 

68. Minoshima S, Frey KA, Foster NL, Kuhl DE. Preserved pontine glucose metabolism in Alzheimer disease: a reference region for functional brain image (PET) analysis. J Comput Assist Tomogr 1995; 19: 541-547. 

69. Ishii K, Sasaki M, Kitagaki H, et al. Reduction of cerebellar glucose metabolism in advanced Alzheimer's disease. J Nucl Med 1997; 38: 925-928. 

70. Weisgraber KH. Apolipoprotein E: Structure-function rela-tionship. Adv Protein Chem 1994; 45: 249-302. 

71 . Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261 : 921-923. 

72. Yamagata Z, Asada T, Kinoshita A, et al. Distribution of apolipoprotein E gene polymorphisms in Japanese patients with Alzheimer's disease and in Japanese centenarians. Hum Hered 1996; 47: 22-26. 

73. Nagy Z, Esiri MM, Jobst KA, et al. Influence of the Apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer's disease. Neuroscience 1995; 69: 757-761 . 

74. Polvikoski T, Sulkava R, Haltia M, et al. Apolipoprotein E, dementia, and cortical deposition of B-amyloid protein. N Engl J Med 1995; 333: 1242-1247. 

75. Bales KR, Verina T, Dodel RC, et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nature Genet 1997; 17: 263-264. 

76. Reiman EM, Caselli RJ, Yun LS, et al. Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 1996; 334: 752-758. 

77. Craft S, Teri L, Edland SD, Kukull WA, et al. Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease. Neurology 1998; 51 : 149-153. 

78. Growdon JH, 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. 

79. Gomez-Isla T, West HL, Rebeck GW, et al. Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer's disease. Ann Neurol 1996; 39: 62-70. 

80. Slooter AJ, Houwing-Duistermaat JJ, van Harskamp F, et a]. Apolipoprotein E genotype and progression of Alzheimer' s disease: the Rotterdam Study. J Neurol 1999; 246: 304-308. 

81 . Corder EH, Jelic V, Basun H, et al. No difference in cerebral glucose metabolism in patients with Alzheimer's disease and differing apolipoprotein E genotypes. Arch Neurol 1997; 54: 273-277. 

82. Hirono N, Mori E, Yasuda M, Ishii K, et al. Lack of association of apolipoprotein E epsilon4 allele dose with cerebral glucose metabolism in Alzheimer disease. Alzheimer Dis Assoc Disord 1998; 12: 362-367. 

83. Frisoni GB, Govoni S, Geroldi C, et al. Gene dose of the epsilon 4 allele of apolipoprotein E and disease progression in sporadic late-onset Alzheimer's disease. Ann Neurol 1995; 37: 596-604. 

84, van Dyck CH, Gelernter J, MacAvoy MG, et al. Absence of an apolipoprotein E epsilon4 allele is associated with increased parietal regional cerebral blood flow asymmetry in Alzheimer disease. Arch Neurol 1998; 55: 1460-1466. 

85. Stem Y, Brandt J, Albert M, et al. The absence of an apo-lipoprotein e4 allele is associated with a more aggressive form of Alzheimer disease. Ann Neurol 1997; 41 : 615-620. 

86. Soininen H, Partanen K, Pitkanen A, et al. Decreased hippocampal volume asymmetry on MRIs in nondemented elderly subjects carrying the apolipoprotein E e4 allele. Neurology 1995; 45: 391-392. 

87. Tohgi H.Takahashi S, Kato E, et al. Reduced size of right hippocampus in 39- to 80-year-old normal subjects carrying the apolipoprotein E e4 allele. Neurosci Lett 1997; 236: 2l-24. 

88. Lehtovirta M,Soininen H,Laakso MP, et al. SPECT and MRI analysis in Alzheimer's disease: relation to the apolipoprotein E e4 allele. J Neurol Neurosurg Psychiatry 1996; 60: 644-649. 

89. Arai H, Higuchi S, Muramatsu T, Iwatsubo T, Sasaki H, Trojanowski JQ. Apolipoprotein E gene in diffuse Lewy body disease with or without co-existing Alzheimer's disease. Lancet 1994; 344: 1307. 

90. Albin RL, Minoshima S, D'Amato CJ, Frey KA, Kuhl DA, Sima AA. Fluoro-deoxyglucose positron emission tomography in diffuse Lewy body disease. Neurology 1996; 47: 462-466. 

91 . Francis Pr, palmar AM, Snape M, Wlcock GK. The cholinergic hypothesis of Alzheimer's disease: a review of progress. J Neurol Neurosurg Psychiatry 1999; 66: 137-147. 

92. Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Neurology 1998; 50: 136-145. 

93. Rogers SL, Doody RS, Mohs R, et al. Donepezil improves cognition and global function in Alzheimer disease. Arch Intern Med 1998; 158: 1021-l031 . 

94. Warren S, Hier DB, Pavel D. Visual form of Alzheimer's disease and its response to anticholinesterase therapy. J Neuroimaging 1998; 8: 249-252.

95. Mega MS, Dinov ID, Lee L, et al. Orbital and dorsolateral frontal perfusion defect associated with behavioral response to cholinesterase inhibitor therapy in Alzheimer's disease. J Neuropsychiatry Clin Neurosic 2000; 12: 209-218.
 
96. Staff RT, Gemmell HG, Shanks MF, Murray AD, Venneri A. Changes in the rCBF images of patients with Alzheimer's disease receiving Donepezil therapy. Nucl Med Commun 2000; 21 : 37-4l. 

97. Irie T, Fukushi K, Akimoto Y, et al. Design and evaluation of radioactive acetylcholine analogs for mapping brain acetylcholinesterase (AchE) in vivo. Nucl Med Biol 1994; 21 : 801-808. 

98. Kuhl DE, Koeppe RA, Minoshima S, et al. In vivo mapping of cerebral acetylcholinestrase acitivity in aging and Alzheimer's disease. Neurology 1 999; 52: 691-699. 

99. Shinotoh H, Namba H. Fukushi K, et al. Progressive loss of cortical acetylcholinesterase activity in association with cognitive decline in Alzheimer's disease: a positron emission tomography study. Ann Neurol 2000; 48: 194-200.
 
100. Kuhl DE, Minoshima S, Frey KA, Foster NL, Kilbourn MR, Koeppe RA. Limited donepezil inhibition of acetylcholinesterase measured by positron emission tomography in living Alzheimer cerebral cortex. Ann Neurol 2000; 48: 391-395.