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Relationship between cholinergic medication and Alzheimer-type pathology

In PD long-term administration of drugs with an anticholinergic action is associated with increased Alzheimer-type pathology, with increased plaques and tangles [71]. Conversely, it has also been demonstrated that long-term exposure to nicotine (tobacco use) is associated with reduced AD pathology (Ap deposition) [72] and in the normal elderly to a greater preservation of neur on numbers in the substantia nigra. There is therefore a potential for the development of drugs which act selectively at muscarinic receptors, both neuroprotective (anti-Alzheimer pathology) Ml agonists [73] and therapeutically at other muscarinic receptor subtypes [74].

It was predicted in 1990 [75] ‘that the cholinergic correlates of mental impairment in senile dementia of Lewy body type [and PD-D] together with the relative absence of cortical neurofibrillary tangles and evidence for postsynaptic cholinergic receptor compensation raise the question of whether this type of dementia may be more amenable to cholinotherapy than classical AD. It was also recognized that the presence of visual hallucinations in the symptom profile would be diagnostic of greater cholinergic compromise [50, 51] and predicted a reliable response to cholinergic medication in these patients [76]. Activation of cholinergic receptors was recognized to be pro-cognitive, especially by improving attention [77, 78].

Glutamate

Excitatory amino acid transmission occurs between several components of the basal ganglia circuitry which are affected in PD-D, and excitotoxic mechanisms have been implicated in the progression of the disease. In PD there is increased output from the subthalamic nucleus, and glutamatergic drive from the subthalamic nucleus may be one of the compensatory mechanisms which begins to fail with disease progression to PD-D. Kashani et al. [79] found expression of the vesicular glutamate transporters VGLUTl and VGLUT2 to be increased by 24 and 29%, respectively, in the putamen of patients with parkinsonism; by contrast, VGLUTl was decreased in the prefrontal and temporal cortex of PD patients (by about 50%). The authors concluded that these findings demonstrate the existence of profound alterations of glutamatergic transmission in PD, which may contribute to the motor and cognitive impairments associated with the disease. A limitation of this study was that the extent of dementia was not assessed. There have been few investigations of glutamate markers in the Lewy body dementias. No change was shown in glutamate transporter protein in the cortex in two DLB cases [80], no change in N-methyl- D-aspartate (NMDA) receptor immunoreactivity in the entorhinal cortex and hippocampus

[81], and no reduction in glutamate in cerebrospinal fluid (CSF) [82]. However, in other studies in DLB, GluR2/3 AMPA receptor immunoreactivity was decreased in the entorhinal cortex and hippocampus [81], and metabotropic mGluR1 and mGluR5 were reduced [83]. The mGluR5 receptor is increased in animal models of PD with dyskinesia [84] and seems to be reduced in the striatum and cortex in PD patients without dyskinesia compared with both PD with dyskinesia and controls. Further studies are needed to determine the extent of the changes in glutamate receptors in PD-D.

Zn2 + is released at glutamatergic terminals, where it acts as a neuromodulator of glutamatergic transmission and is important for the maintenance of cognition [85]. We have recently shown reductions in ZnT3 (see Fig. 14.4), the major ion pump responsible for controlling this release of Zn2 +> in the prefrontal cortex of PD-D patients [86].

ZnT3 levels are reduced in postmortem tissue from PD-D, DLB, and AD patients relative to controls

Fig. 14.4 ZnT3 levels are reduced in postmortem tissue from PD-D, DLB, and AD patients relative to controls.

 
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