Striatal dopaminergic markers in dementia with Lewy bodies, Alzheimer's and Parkinson's diseases: rostrocaudal distribution.
Dementia with Lewy bodies (DLB) is a neuropsychiatric disease associated with extrapyramidal features which differ from those of Parkinson's disease, including reduced effectiveness of L-dopa and severe sensitivity reactions to neuroleptic drugs. Distinguishing Alzheimer's disease from DLB is clinically relevant in terms of prognosis and appropriate treatment. Dopaminergic activities have been investigated at coronal levels along the rostrocaudal striatal axis from a post-mortem series of 25 DLB, 14 Parkinson's disease and 17 Alzheimer's disease patients and 20 elderly controls. [(3)H]Mazindol binding to the dopamine uptake site was significantly reduced in the caudal putamen in DLB compared with controls (57%), but not as extensively as in Parkinson's disease (75%), and was unchanged in Alzheimer's disease. Among three dopamine receptors measured (D1, D2 and D3), the most striking changes were apparent in relation to D2. In DLB, [(3)H]raclopride binding to D2 receptors was significantly reduced in the caudal putamen (17%) compared with controls, and was significantly lower than in Parkinson's disease at all levels. D2 binding was significantly elevated at all coronal levels in Parkinson's disease compared with controls, most extensively in the rostral putamen (71%). There was no change from the normal pattern of D2 binding in Alzheimer's disease. The only significant alteration in D1 binding ([(3)H]SCH23390) in the groups examined was an elevation (30%) in the caudal striatum in Parkinson's disease. There were no differences in D3 binding, measured using [(3)H]7-OH-DPAT, in DLB compared with controls. A slight, significant decrease in D3 binding in the caudal striatum of Parkinson's disease (13%) patients and an increase in Alzheimer's disease (20%) in the dorsal striatum at the level of the nucleus accumbens were found. The concentration and distribution of dopamine were disrupted in both DLB and Parkinson's disease, although in the caudate nucleus the loss of dopamine in DLB was uniform whereas in Parkinson's disease the loss was greater caudally. In the caudal putamen, dopamine was reduced by 72% in DLB and by 90% in Parkinson's disease. The homovanillic acid : dopamine ratio, a metabolic index, indicated compensatory increased turnover in Parkinson's disease, which was absent in DLB despite the loss of substantia nigra neurons (49%), dopamine and uptake sites. These differences between DLB, Parkinson's disease and Alzheimer's disease may explain some characteristics of the extrapyramidal features of DLB and its limited response to L-dopa and severe neuroleptic sensitivity. The distinct changes in the rostrocaudal pattern of expression of dopaminergic parameters are relevant to the interpretation of the in vivo imaging and diagnosis of DLB.
Piggott
M A
MA
MRC Neurochemical Pathology Unit, Department of Neuropathology, Old Age Psychiatry, Newcastle General Hospital, Newcastle-upon-Tyne, NE4 6BE, UK. M.A.Piggott@ncl.ac.uk
Marshall
E F
EF
Thomas
N
N
Lloyd
S
S
Court
J A
JA
Jaros
E
E
Burn
D
D
Johnson
M
M
Perry
R H
RH
McKeith
I G
IG
Ballard
C
C
Perry
E K
EK
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001345:Autoradiography; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D003704:Dementia / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008454:Mazindol / Q000493:pharmacokinetics; D008875:Middle Aged; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D020891:Raclopride; D011954:Receptors, Dopamine / Q000032:analysis / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000032:analysis / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000032:analysis / Q000378:metabolism; D050637:Receptors, Dopamine D3; D012457:Salicylamides / Q000493:pharmacokinetics; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics; D014316:Tritium
C493593:DRD3 protein, human; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D012457:Salicylamides; D013764:Tetrahydronaphthalenes; D014316:Tritium; D020891:Raclopride; D008454:Mazindol; C031349:7-hydroxy-2-N,N-dipropylaminotetralin; D004298:Dopamine; D006719:Homovanillic Acid