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PET: Studies in dementia
P.yw~hiutry Rtwurc~h. 29:353-355
353
Elsevier
PET: Studies R.S.J.
in Dementia
Frackowiak
Positron tomography has been used extensively in the last 8 years in the exploration of the dementias in life. The initial years centered on studies of cerebral energy metabolism both with 150-labeled compounds and ‘XFDG (Frackowiak, 1987). The initial observations strongly suggested a focal emphasis of dysfunction in early Alzheimer’s disease. The hypometabolism was most prominent in the posterior parietal and temporal regions. This was in the context of a more generalized decline, however, with relative sparing of the occipital and primary motor-sensory cortex (Frackowiak et al., 198 I). The depression of cerebral energy metabolism correlated with clinical measures of disease severity. Severe disease was associated with a further global decline as well as a more profound focal decrease in frontal areas to match those in the posterior parietal and temporal regions. More recently, studies in the subcortical dementias have indicated differential patterns of dysmetabolism. In Huntington’s disease, the caudate nuclei are affected early in the disease (Kuhl et al., 1982). There is even a suggestion in the literature that presymptomatic carriers of the Huntington gene may be distinguished by early caudate hypometabolism (Mazziotta et al., 1985). Global depression of metabolism in the cortex is seen only in later stages of the disease. In progressive supranuclear palsy of Steele-Richardson-Olszewski, a pronounced decline in frontal metabolism has been described, though other authors have suggested a more generalized decrease in energy metabolism (D’Antona et al., 1985; Foster et al., 1988; Leenders et al., 1988). The emphasis, however, is always frontal. In Parkinson’s disease, associated with severe dementia, hypometabolism has been noted in the same areas as those found in Alzheimer’s disease (Kuhl et al., 1984). It is as yet not clear whether this represents the coincidental occurrence of two common diseases of the elderly or whether Parkinson’s disease in its late stages may affect these regions of the cortex specifically. Studies of more subtle neuropsychological deficits, much more commonly encountered in Parkinsonian patients, have not been systematically carried out yet. Pilot studies are underway at the MRC Cyclotron Unit. Energy metabolism and cerebral hemodynamics have also been studied in multiinfarct dementias (Frackowiak et al., 1981; Benson et al., 1983; Metter et al., 1985). The defects tend to be focal and scattered throughout the cortex in discrete patches. There is no evidence, between acute ischemic episodes, of any flow-limited metabolism. In the occasional patient with extensive extracranial occlusive vascular disease, considerable hemodynamic decompensation, as measured by the CBFjCBV
Reprint requests to: R.S.J. OHS, United Kingdom. 016%1781/89/$03.50
Frackowiak,
MRC
@ 1989 Elsevier Scientific
Cyclotron
Unit,
Hammersmith
Publishers Ireland Ltd.
Hospital,
London
W 12
354 ratio, has been described (Gibbs et al., 1986). The predisposition to further ischemic events in such patients is not known. Studies of the dopaminergic system in the subcortical dementias have indicated intriguing differences among Huntington’s disease, Alzheimer’s disease, and the Steele-Richardson-Olszewski syndrome. In Parkinson’s disease, the uptake of ‘SF-t.dopa into the striatum is grossly disturbed, particularly in the putamen (Leenders et al., 19866). In contrast, the uptake of rrC-N-methylspiperone appears to be normal in these regions (Leenders et al., 1986~) (rrC-N-spiperone is a D, receptor ligand). Binding in the various stages of Parkinson’s disease and in relation to t.-dopa medication has not been extensively studied to date. In Steele-Richardson-Olszewski syndrome, binding of the D, receptor ligand 7hbromospiperone has been shown to be grossly diminished (Baron et al., 1986) and the uptake of ‘RF-t.-dopa is also decreased but not to the same degree as in Parkinson’s disease (Leenders et al., 1988). In Huntington’s disease, in contrast, there is normal IXF-t.-dopa uptake but, in the one case studied, a marked decline of rrC-N-methylspiperone binding (Leenders et al., 1986~). These patterns, if they are confirmed, could prove sensitive indicators of subcortical pathology in the cognitive decline associated with these disorders. rXF-~.dopa, combined with measurement of energy metabolism, may provide a means of early detection of Alzheimer’s disease in the future. Studies in other dementias have also been described, but less frequently. In Pick’s disease there is marked frontal and frontotemporal hypometabolism (Kamo et al., 1987). There have been preliminary observations in chronic focal progressive aphasia suggesting very focal regions of hypometabolism in areas associated with language function (Chawluk et al., 1986). The new generation of positron cameras with fine resolution and multislice capability raises the expectation that the preliminary findings described above may now be refined to a degree that observations may be made in early disease and localized more specifically in anatomical terms. The capacity to follow dysmetabolism with time in degenerative disorders such as Alzheimer’s disease is of great interest in that it permits a more precise study of the evolution of degeneration in life. This, of course, is not possible without resort to biopsy in man, as there is no animal model of this disorder. It is hoped that in the future specific tracers of other neurotransmitter systems than the dopaminergic system will become available. This raises the possibility of investigating the patterns of neurochemical degeneration in various degenerative diseases, which may give more fundamental insights into their pathogenesis. References B.; Loc’h, C.; Cambon, H.; Sgouropoulos. P.; Bonnet, M.; and Agid, Y. bromospiperone binding sites demonstrated by positron tomography in progressive supranuclear palsy. Journal of Cerebral Blood Flow and Metabolism. 6: 13I, I%%. Benson, D.F.; Kuhl, D.E.; Hawkins, R.A.; Phelps. M.E.; Cummings, J.L.; and Tsai. S.Y. The fluorodeoxyglucose IXF scan in Alzheimer’s disease and multi-infarct dementia. Archives Baron, J.C.; MaTiere,
Loss of striatal(7hBr)
40:7 I I, 1983. Chawluk, J.B.; Mesulam, M.M.; Hurtig, H.; Kushner, M.; Weintraub, S.; Saykin, A.; Rubin, N.; Alavi, A.; and Reivich, M. Slowly progressive aphasia without generalized dementia: Studies with positron emission tomography. Annals o/‘Neurology. 19:6X, 1986. of’ Neurology,
355 D’Antona, R.; Baron, J.C.; Samson, Y.; Serdaru, M.; Viader, F.; Agid, Y.; and Cambier, J. Subcortical dementia: Frontal cortex hypometabolism detected by positron tomography in patients with progressive supranuclear palsy. Brain, 108:785, 1985. Foster, N.L.; Gilman, S.; Berent, S.; Morin, E.M.; Brown, M.B.; and Koeppe, R.A. Cerebral hypometabolism in progressive supranuclear palsy studied with positron emission tomography. Annuls of’ Neurology, 24:399, 1988. Frackowiak, R.S.J. Measurement and imaging of cerebral function in ageing and dementia. In: Swaab, D.F.; Fliers, E.; Mirmiran, W.A.; van Cool, W.A.; and van Haaren, F., eds. Age&g qfthe Brain and Dementia: Progress in Brain Research. Amsterdam: Elsevier Science Publishers, 1987. Frackowiak, R.S.J.; Pozzilli, C.; Legg, N.J.; DuBoulay, G.H.; Marshall, J.; Lenzi, G.L.; and Jones, T. Regional cerebral oxygen supply and utilization in dementia: A clinical and physiological study with oxygen-l 5 and positron tomography. Brain, 104:753, 198 I. Gibbs, J.M.; Frackowiak, R.S.J.; and Legg, N.J. Regional cerebral blood flow and oxygen metabolism in dementia due to vascular disease. Gerontology, 32 (Suppl. I): 84, 1986. Kamo, H.; McGeer, P.L.; Harrop, R.; McGeer, E.C.; Calne, D.B.; Martin, W.R.W.; and Pate, B.D. Positron emission tomography and histopathology in Pick’s disease. Neurology, 37:439, 1987. Kuhl, D.E.; Metter, E.J.; Riege, W.H.; and Markham, C.H. Patterns of cerebral glucose utilization in Parkinson’s disease and Huntington’s disease. Anna/s oj Neurology, 15 (Suppl.): 119, 1984. Kuhl, D.E.; Phelps, M.E.; Markham, C.H.; Metter, E.J.; Riege, W.H.; and Winter, E.J. Cerebral metabolism and atrophy in Huntington’s disease determined by lXFDG and computed tomographic scans. Annals OJ Neurology, I2:425, 1982. Leenders, K.L.; Frackowiak, R.S.J.; and Lees, A.J. Steele-Richardson-Olszewski syndrome: Brain energy metabolism, blood flow and fluorodopa uptake measured by positron emission tomography. Brain, I I l:615, 1988. Leenders, K.L.; Frackowiak, R.S.J.; Quinn, N.; and Marsden, C.D. Brain energy metabolism and dopaminergic function in Huntington’s disease measured in vivo using positron emission tomography. Movement Disorders. I :69, I986a. Leenders, K.L.; Palmer, A.J.; Quinn, N.; Clark, J.C.; Firnau, G.; Garnett, E.S.; Nahmias, C.; Jones, T.; and Marsden, C.D. Brain dopamine metabolism in patients with Parkinson’s disease measured with positron emission tomography. Journal of Neurology, Neurosurgery and Psychiatry. 49:853, 19866. Leenders, K.L.; Palmer, A.J.; Turton, D.; Quinn, N.; Firnau, G.; Garnett, E.S.; Nahmias, C.; Jones, T.; and Marsden, C.D. Dopa uptake and dopamine receptor binding visualized in the human brain in vivo. In: Fahn, S.; Marsden, C.D.; Jenner, P.; and Teychenne, P., eds. Recent Developments in Parkinson’s Disease. New York: Raven Press, 1986~. p. 103 Mazziotta, J.C.; Wapenski, J.; Phelps, M.E.; Riege, W.; Baxter, L.; Fullerton, A.; Kuhl, D.E.; Bradley, W.; Selin, C.; and Sumida, R. Cerebral glucose utilization and blood flow in Huntington’s disease: Symptomatic and at-risk subjects. JournalofCerehral Blood Flow and Metabolism, 5 (Suppl.):25, 1985. Metter, E.J.; Mazziotta, J.C.; Itabashi, H.H.; Mankovich, J.J.; Phelps, M.E.; and Kuhl, D.E. Comparison of glucose metabolism, X-ray CT and post-mortem data in a patient with multiple cerebral infarcts. Neurology. 35: 1695, 1985.
353
Elsevier
PET: Studies R.S.J.
in Dementia
Frackowiak
Positron tomography has been used extensively in the last 8 years in the exploration of the dementias in life. The initial years centered on studies of cerebral energy metabolism both with 150-labeled compounds and ‘XFDG (Frackowiak, 1987). The initial observations strongly suggested a focal emphasis of dysfunction in early Alzheimer’s disease. The hypometabolism was most prominent in the posterior parietal and temporal regions. This was in the context of a more generalized decline, however, with relative sparing of the occipital and primary motor-sensory cortex (Frackowiak et al., 198 I). The depression of cerebral energy metabolism correlated with clinical measures of disease severity. Severe disease was associated with a further global decline as well as a more profound focal decrease in frontal areas to match those in the posterior parietal and temporal regions. More recently, studies in the subcortical dementias have indicated differential patterns of dysmetabolism. In Huntington’s disease, the caudate nuclei are affected early in the disease (Kuhl et al., 1982). There is even a suggestion in the literature that presymptomatic carriers of the Huntington gene may be distinguished by early caudate hypometabolism (Mazziotta et al., 1985). Global depression of metabolism in the cortex is seen only in later stages of the disease. In progressive supranuclear palsy of Steele-Richardson-Olszewski, a pronounced decline in frontal metabolism has been described, though other authors have suggested a more generalized decrease in energy metabolism (D’Antona et al., 1985; Foster et al., 1988; Leenders et al., 1988). The emphasis, however, is always frontal. In Parkinson’s disease, associated with severe dementia, hypometabolism has been noted in the same areas as those found in Alzheimer’s disease (Kuhl et al., 1984). It is as yet not clear whether this represents the coincidental occurrence of two common diseases of the elderly or whether Parkinson’s disease in its late stages may affect these regions of the cortex specifically. Studies of more subtle neuropsychological deficits, much more commonly encountered in Parkinsonian patients, have not been systematically carried out yet. Pilot studies are underway at the MRC Cyclotron Unit. Energy metabolism and cerebral hemodynamics have also been studied in multiinfarct dementias (Frackowiak et al., 1981; Benson et al., 1983; Metter et al., 1985). The defects tend to be focal and scattered throughout the cortex in discrete patches. There is no evidence, between acute ischemic episodes, of any flow-limited metabolism. In the occasional patient with extensive extracranial occlusive vascular disease, considerable hemodynamic decompensation, as measured by the CBFjCBV
Reprint requests to: R.S.J. OHS, United Kingdom. 016%1781/89/$03.50
Frackowiak,
MRC
@ 1989 Elsevier Scientific
Cyclotron
Unit,
Hammersmith
Publishers Ireland Ltd.
Hospital,
London
W 12
354 ratio, has been described (Gibbs et al., 1986). The predisposition to further ischemic events in such patients is not known. Studies of the dopaminergic system in the subcortical dementias have indicated intriguing differences among Huntington’s disease, Alzheimer’s disease, and the Steele-Richardson-Olszewski syndrome. In Parkinson’s disease, the uptake of ‘SF-t.dopa into the striatum is grossly disturbed, particularly in the putamen (Leenders et al., 19866). In contrast, the uptake of rrC-N-methylspiperone appears to be normal in these regions (Leenders et al., 1986~) (rrC-N-spiperone is a D, receptor ligand). Binding in the various stages of Parkinson’s disease and in relation to t.-dopa medication has not been extensively studied to date. In Steele-Richardson-Olszewski syndrome, binding of the D, receptor ligand 7hbromospiperone has been shown to be grossly diminished (Baron et al., 1986) and the uptake of ‘RF-t.-dopa is also decreased but not to the same degree as in Parkinson’s disease (Leenders et al., 1988). In Huntington’s disease, in contrast, there is normal IXF-t.-dopa uptake but, in the one case studied, a marked decline of rrC-N-methylspiperone binding (Leenders et al., 1986~). These patterns, if they are confirmed, could prove sensitive indicators of subcortical pathology in the cognitive decline associated with these disorders. rXF-~.dopa, combined with measurement of energy metabolism, may provide a means of early detection of Alzheimer’s disease in the future. Studies in other dementias have also been described, but less frequently. In Pick’s disease there is marked frontal and frontotemporal hypometabolism (Kamo et al., 1987). There have been preliminary observations in chronic focal progressive aphasia suggesting very focal regions of hypometabolism in areas associated with language function (Chawluk et al., 1986). The new generation of positron cameras with fine resolution and multislice capability raises the expectation that the preliminary findings described above may now be refined to a degree that observations may be made in early disease and localized more specifically in anatomical terms. The capacity to follow dysmetabolism with time in degenerative disorders such as Alzheimer’s disease is of great interest in that it permits a more precise study of the evolution of degeneration in life. This, of course, is not possible without resort to biopsy in man, as there is no animal model of this disorder. It is hoped that in the future specific tracers of other neurotransmitter systems than the dopaminergic system will become available. This raises the possibility of investigating the patterns of neurochemical degeneration in various degenerative diseases, which may give more fundamental insights into their pathogenesis. References B.; Loc’h, C.; Cambon, H.; Sgouropoulos. P.; Bonnet, M.; and Agid, Y. bromospiperone binding sites demonstrated by positron tomography in progressive supranuclear palsy. Journal of Cerebral Blood Flow and Metabolism. 6: 13I, I%%. Benson, D.F.; Kuhl, D.E.; Hawkins, R.A.; Phelps. M.E.; Cummings, J.L.; and Tsai. S.Y. The fluorodeoxyglucose IXF scan in Alzheimer’s disease and multi-infarct dementia. Archives Baron, J.C.; MaTiere,
Loss of striatal(7hBr)
40:7 I I, 1983. Chawluk, J.B.; Mesulam, M.M.; Hurtig, H.; Kushner, M.; Weintraub, S.; Saykin, A.; Rubin, N.; Alavi, A.; and Reivich, M. Slowly progressive aphasia without generalized dementia: Studies with positron emission tomography. Annals o/‘Neurology. 19:6X, 1986. of’ Neurology,
355 D’Antona, R.; Baron, J.C.; Samson, Y.; Serdaru, M.; Viader, F.; Agid, Y.; and Cambier, J. Subcortical dementia: Frontal cortex hypometabolism detected by positron tomography in patients with progressive supranuclear palsy. Brain, 108:785, 1985. Foster, N.L.; Gilman, S.; Berent, S.; Morin, E.M.; Brown, M.B.; and Koeppe, R.A. Cerebral hypometabolism in progressive supranuclear palsy studied with positron emission tomography. Annuls of’ Neurology, 24:399, 1988. Frackowiak, R.S.J. Measurement and imaging of cerebral function in ageing and dementia. In: Swaab, D.F.; Fliers, E.; Mirmiran, W.A.; van Cool, W.A.; and van Haaren, F., eds. Age&g qfthe Brain and Dementia: Progress in Brain Research. Amsterdam: Elsevier Science Publishers, 1987. Frackowiak, R.S.J.; Pozzilli, C.; Legg, N.J.; DuBoulay, G.H.; Marshall, J.; Lenzi, G.L.; and Jones, T. Regional cerebral oxygen supply and utilization in dementia: A clinical and physiological study with oxygen-l 5 and positron tomography. Brain, 104:753, 198 I. Gibbs, J.M.; Frackowiak, R.S.J.; and Legg, N.J. Regional cerebral blood flow and oxygen metabolism in dementia due to vascular disease. Gerontology, 32 (Suppl. I): 84, 1986. Kamo, H.; McGeer, P.L.; Harrop, R.; McGeer, E.C.; Calne, D.B.; Martin, W.R.W.; and Pate, B.D. Positron emission tomography and histopathology in Pick’s disease. Neurology, 37:439, 1987. Kuhl, D.E.; Metter, E.J.; Riege, W.H.; and Markham, C.H. Patterns of cerebral glucose utilization in Parkinson’s disease and Huntington’s disease. Anna/s oj Neurology, 15 (Suppl.): 119, 1984. Kuhl, D.E.; Phelps, M.E.; Markham, C.H.; Metter, E.J.; Riege, W.H.; and Winter, E.J. Cerebral metabolism and atrophy in Huntington’s disease determined by lXFDG and computed tomographic scans. Annals OJ Neurology, I2:425, 1982. Leenders, K.L.; Frackowiak, R.S.J.; and Lees, A.J. Steele-Richardson-Olszewski syndrome: Brain energy metabolism, blood flow and fluorodopa uptake measured by positron emission tomography. Brain, I I l:615, 1988. Leenders, K.L.; Frackowiak, R.S.J.; Quinn, N.; and Marsden, C.D. Brain energy metabolism and dopaminergic function in Huntington’s disease measured in vivo using positron emission tomography. Movement Disorders. I :69, I986a. Leenders, K.L.; Palmer, A.J.; Quinn, N.; Clark, J.C.; Firnau, G.; Garnett, E.S.; Nahmias, C.; Jones, T.; and Marsden, C.D. Brain dopamine metabolism in patients with Parkinson’s disease measured with positron emission tomography. Journal of Neurology, Neurosurgery and Psychiatry. 49:853, 19866. Leenders, K.L.; Palmer, A.J.; Turton, D.; Quinn, N.; Firnau, G.; Garnett, E.S.; Nahmias, C.; Jones, T.; and Marsden, C.D. Dopa uptake and dopamine receptor binding visualized in the human brain in vivo. In: Fahn, S.; Marsden, C.D.; Jenner, P.; and Teychenne, P., eds. Recent Developments in Parkinson’s Disease. New York: Raven Press, 1986~. p. 103 Mazziotta, J.C.; Wapenski, J.; Phelps, M.E.; Riege, W.; Baxter, L.; Fullerton, A.; Kuhl, D.E.; Bradley, W.; Selin, C.; and Sumida, R. Cerebral glucose utilization and blood flow in Huntington’s disease: Symptomatic and at-risk subjects. JournalofCerehral Blood Flow and Metabolism, 5 (Suppl.):25, 1985. Metter, E.J.; Mazziotta, J.C.; Itabashi, H.H.; Mankovich, J.J.; Phelps, M.E.; and Kuhl, D.E. Comparison of glucose metabolism, X-ray CT and post-mortem data in a patient with multiple cerebral infarcts. Neurology. 35: 1695, 1985.