Progressive Supranuclear Palsy

Metabolic Studies

Neuropathological criteria for PSP include the accumulation of intraneuronal globose neurofibril-lary tangles in and often atrophy of the following structures: pallidum and subthalamic nucleus, substantia nigra, pontine tegmentum, oculomotor and pontine nuclei, striatum, and prefrontal and precentral cortices (34). These pathological findings have been reflected by changes in function observed in a number of PET and SPECT studies using 18FDG or blood flow markers (35-41). The studies reported ~25% decreases of regional cerebral metabolism in the frontal cortex, striatum, and thalamus.

Two more recent studies localized the metabolic changes in PSP using SPM (statistical parametric mapping) (42), which explores focal changes in brain metabolism without having to make a priori hypotheses. This confirmed the earlier studies using region of interest analysis but highlighted the involvement of the frontal eye fields in premotor cortex (43,44).

The decreases in frontal metabolism (hypofrontality) may reflect primary frontal cortical pathology but are more likely to arise because of pallidal degeneration since internal pallidal neurons project via the ventrolateral thalamus to premotor and prefrontal areas (45).

Dopaminergic System

In PSP the nigrostriatal dopaminergic projections are uniformly affected and caudate and putamen dopamine content is equivalently reduced to 10-25 % of normal levels (46,47).

The uniform degeneration of nigrostriatal dopaminergic projections is reflected by findings from PET and SPECT studies of the presynaptic dopaminergic system in PSP. The first [18F]dopa PET study in PSP found a decrease in striatal dopamine formation and storage that correlated with disease severity but was unable to clearly separate caudate and putamen signals owing to the low 1.5-cm resolution of the PET camera (36). Using higher-resolution cameras it became possible to show that, in contrast to PD, the Ki values in the PSP group were uniformly reduced in putamen and caudate to ~40% of normal values (48). Applying discriminant analysis the differential involvement of the caudate [18F]dopa uptake has allowed 90% of clinically probable PSP patients to be seperated from PD (22). A similar difference in the degree of caudate involvement between PSP and PD was found using the PET dopamine transporter marker [11C]-WIN 35,428 (49). Another interesting application of [18F]dopa PET has been the demonstration of reduced striatal [18F]dopa uptake in 5 out of 15 asymptomatic members of a PSP kindred; one of these subjects developed clinical PSP 2 yr after the scan, thus indicating that [18F]dopa PET has the ability to detect familial PSP preclinically (43).

[123I]p-CIT and FP-CIT SPECT have also been used in PSP to demonstrate presynaptic degeneration of dopamine terminals. Although it has been possible to demonstrate the "relative caudate sparing" in PD compared to PSP, especially in relatively early cases (50,51), other groups have found these approaches of limited value in discriminating PSP from PD (27).

D2 receptor binding in PSP patients has been examined as early as 1986 using the D2 antagonist [76Br]bromospiperone (52). A mean fall of 24% in equilibrium striatum/cerebellar uptake ratios was observed, but 50% of their PSP cases had striatal D2 binding within the normal range.

Brooks and colleagues studied nine PSP patients with [11C]raclopride PET (53); the PSP group showed 24% and 9% significant reductions of tracer caudate and putamen:cerebellar uptake ratios, and again only 50% of patients had individually reduced uptake ratios. In a larger series of 32 patients with probable PSP, 20 of these subjects showed reduced basal ganglia/frontal cortex [123I-IBZM signal ratios, indicating a reduction of D2 receptors in approx two-thirds of PSP patients (54). A smaller number of patients with probable PSP (n = 6) were scanned with the D2 marker [123I]iodobenzfuran (IBF SPECT); 8% and 21% reductions of binding potential in the posterior putamen and caudate were found, which failed to reach statistical significance (24).

These PET and SPECT findings of moderate reductions of striatal D2 receptor binding in PSP are in agreement with neuropatholgical findings reporting ~30% reductions in D2 density in the caudate and putamen of these patients (55).

Cholinergic, Opioid, and Benzodiazepine Binding

Burn and colleagues examined striatal opioid binding in PSP (29). [11C]diprenorphine binding was reduced in all six PSP patients. Interestingly, caudate and putamen were equally affected, whereas in MSA-P patients caudate binding remained normal.

When using N-methyl-4-[nC]piperidyl and PET to measure acetylcholinesterase (AChE) activity in 12 patients with PSP, Shinotoh and coworkers found a prominent reduction (-38%) of thalamic

AChE activity whereas the cortical activity was only slightly reduced (56). Using 11C-physostigmine PET, Pappata and colleagues have also reported reduced striatal AChE levels in PSP, which correlated with disability (57).

A recent autoradiographic study in PSP (58) found degeneration of striatal cholinergic and dopam-inergic terminals, whereas central benzodiazepine receptor binding remained unaffected. Since basal ganglia cholinergic terminals seem to degenerate in a selective manner in PSP, striatal VAChT (ace-tylcholine vesicular transporter) reduction may provide a unique neurochemical imaging marker for distinction of PSP from other types of basal ganglia neurodegeneration.

PET and [nC]flumazenil (FMZ), a nonselective central benzodiazepine receptor antagonist, can be used to examine the density of benzodiazepine/GABAA receptors. Since probably all cortical neurons express GABAA receptors, the density of these receptors provides a measure of the integrity of intrinsic cerebral cortical neurons. In a group of 12 PSP patients, a slight reduction of [11C]flumazenil was detected in the anterior cingulate gyrus but no other abnormalities were found (59).

Although it is known from autoradiographic postmortem studies that benzodiazepine binding is reduced in the pallidum and preserved in the striatum of PSP patients (58), the low expression of these receptors in the pallidum and proximity of the putamen probably make current functional imaging techniques too insensitive to detect these changes (60).

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