The present study shows a divergence in the severity of tau pathology between area 24′ and the caudate nucleus of patients with PSP, as well as significant PSP-related alterations in the densities of multiple receptors from different neurotransmitter systems that differentially affected both structures. In the caudate nucleus of PSP brains, densities of pBZ and A1 receptors were higher, and those of kainate and nACh receptors were lower, than in control subjects. In area 24′, NMDA, GABAB, pBZ, and 5-HT2 receptor densities were higher in PSP than in control tissue. Furthermore, clinically relevant PSP subgroups could be differentiated on the basis of their receptor fingerprints.
To our knowledge, this is the first study to show that patients with PSP with frontal and nonfrontal presentations can be differentiated postmortem with a high degree of accuracy on the basis of differences in receptor densities in both the caudate nucleus and area 24′. Receptor fingerprints also segregate mild from moderate to severe tau cases. We are aware that a drawback of our study is the fact that we were not able to assess the effect of medication on receptor densities, owing to the variability in drug therapy among patients.
Tau pathology is the histological hallmark of PSP, though the severity and distribution of tau pathology may differ between PSP subgroups . The cerebral cortex and caudate nucleus are among the regions where the differences in severity are greatest . This divergence in severity of pathology between the cingulate cortex and the caudate nucleus is supported by the present semiquantitative evaluation and is reflected by our receptor data.
The widespread alterations in the GABAergic system highlight its importance in the pathophysiology of PSP. GABAB receptor densities were increased in area 24′ of patients with PSP, but they were unaltered in the caudate nucleus. Because the increased density of GABAB receptors occurred in all PSP subgroups (frontal/nonfrontal and mild/severe tau), they seem to be the most vulnerable receptor type in PSP. Furthermore, the GABAB receptor increase in the midcingulate cortex is of particular interest because its activation is associated with the induction of long-term potentiation  and results in amelioration of the cognitive impairment associated with chronic cerebral hypoperfusion .
BZ binding sites were decreased in the caudate nucleus of patients with PSP only in cases of moderate to severe tau pathology. This decrease may be caused by a loss of GABAergic projection neurons in this PSP subgroup, leading to a reduction of pre- and postsynaptic γ-aminobutyric acid receptor type A (GABAA) and could explain the therapeutic effectivity of BZ agonists . The GABAA receptor density demonstrated by the binding with the agonist [3H]muscimol also showed a decrease, but this did not reach significance (Tables 4 and 5). Because the agonistic binding prefers high-affinity binding sites of the receptor, these data may indicate a shift of the ratio between low- and high-affinity binding sites of the GABAA receptor in PSP.
Densities of pBZ receptors were higher in area 24′ and the caudate nucleus of patients with PSP than in control subjects. This is in line with the increased PK11195 binding in these regions revealed by a positron emission tomography (PET) study  and reflects microglial activation. However, when the cohort was subdivided into frontal/nonfrontal cases or mild/severe tau pathology, consistent alterations were found only in area 24′. Taken together, receptors of the GABAergic system are more affected in area 24′ than in the caudate nucleus, and impairment does not depend on the severity of tau pathology and frontal or nonfrontal clinical type.
Our findings of widespread PSP-related changes in the glutamatergic system may be relevant for potential future treatment strategies in PSP, similar to recent studies in Parkinson’s disease [26, 27]. The divergence in the severity of receptor impairments between cortical and subcortical sites is further supported by our findings regarding NMDA receptors, which were altered only in area 24′. This increase in NMDA receptor densities is probably due to region-specific disease-induced alterations, and not caused by the long-term administration of amantadine, because patients treated with this NMDA receptor antagonist (patients 8 and 12; see Table 3) presented normal NMDA receptor densities. The unchanged NMDA receptor density in the caudate nucleus is in accordance with the one other study investigating NMDA receptors in patients with PSP . Furthermore, we found a decrease of kainate receptor densities but unaltered α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and metabotropic glutamate receptor type 2/3 densities, where up to now no information was available in patients with PSP.
Drugs targeting the cholinergic system have failed to relieve the cognitive and motor impairments of PSP . Interestingly, of the four cholinergic receptor types examined here, only the nACh receptors were found to be altered in the PSP cohort (as a whole and in all subgroups), though only in the caudate nucleus. Our results for nACh and M1 receptors in the caudate nucleus are in line with previous findings . The unaltered caudate nucleus muscarinic cholinergic receptor type 2 (M2) receptor densities, however, contrast with the findings in another postmortem study in which researchers reported reduced M2 receptor densities in the posterior caudate nucleus . The discrepancy may be explained by differences in postmortem delay times (45 h versus 6 h in our study); ligands used (the antagonist [3H]-AFDX 384 versus the agonist [3H]oxotremorine-M in our study); or the rostrocaudal anatomical, neurochemical, and functional differences that characterize the caudate nucleus .
Interestingly, the nACh receptor plays a major role in the control of dopamine release in the caudate nucleus . Consequently, the remarkably strong decrease in nACh receptor densities leads to a reduction of dopamine release, which results in a global impairment of dopaminergic effects in the caudate nucleus of patients with PSP.
The normal density of adrenoceptors in the caudate nucleus and area 24′ in our cases, together with the normal adrenaline levels in various brain regions of patients with PSP as found by Kish et al. , as well as the ineffectiveness of noradrenergic replacement therapies , suggests that this neurotransmitter system does not contribute significantly to the symptomatology of PSP. It must be noted, however, that researchers in the single other autoradiographic study on adrenoceptors in PSP to date found a generalized reduction of adrenoceptor type 2 receptors , though their findings were based on a case report.
The 5-HT2 receptor also emphasizes the divergent severity of alterations between area 24′ and the caudate nucleus in PSP, because it was increased only in the former structure, preferentially in the frontal group. Our results are difficult to compare with those of an in vivo PET imaging study in which investigators reported normal densities of 5-HT2 receptors in the neocortex, but higher concentrations in the putamen , because different regions were examined and different ligands ([18F]altanserin versus [3H]ketanserin in our cases) were used. Furthermore, [18F]altanserin PET does not directly reflect 5-HT2 receptor density, because it is confounded by the uptake of blood-brain barrier-penetrating metabolites and nonspecific binding of [18F]altanserin itself .
The decrease of 5-HT2 receptor densities in the caudate nucleus of PSP brains with moderate to severe tau pathology compared with those with mild tau pathology cannot be explained merely by a more severe neurodegeneration in the former group, because we did not observe an association between tau pathology and 5-HT2 receptor alterations in area 24′. Interestingly, although a differential effect of serotonergic denervation on tau pathology in various brain regions has been described previously, the underlying explanation for this selective vulnerability remains unclear .
Dopaminergic receptors are localized on medium spiny stellate cells. Cells expressing D1 receptors, or D1 colocalized with D2 receptors, preferentially project to the substantia nigra and the internal segment of the globus pallidus, whereas those expressing D2 receptors target the external segment of the globus pallidus . Our finding of unaltered D1 receptor densities is in accordance with previous reports [10, 39], and the unchanged D2 receptor densities described here add to the controversial data concerning this receptor type [10, 11, 39].
A1 receptors are frequently localized presynaptically and control glutamate release. Thus, the significant PSP-related increase of receptor densities in the caudate nucleus may be a plastic reaction to (1) decreased inhibition resulting from BZ binding site downregulation and (2) increased excitation resulting from higher NMDA and lower kainate receptor densities, because the latter can also control glutamate release. The PSP-related increase in A1 receptor densities in the caudate nucleus may be the result of an ongoing inflammatory process because these receptors are expressed in microglia . Furthermore, it could be a compensatory mechanism to counteract the decreased concentrations of the adenosine precursors adenosine diphosphate and adenosine triphosphate measured in the basal ganglia of patients with PSP . Therefore, an intriguing question is whether modulation targeting the adenosine receptors may represent a therapeutic strategy in PSP.