Neurochemical pathology of Parkinson's disease dementia and dementia with Lewy bodies
David Whitfield, Margaret Ann Piggott, Elaine K. Perry, and Paul T. Francis
Introduction
Whether neurotransmitter deficits and related changes in Parkinson’s disease dementia (PD-D) differ in kind or degree compared with those in Parkinson’s disease (PD) is an important question when considering the clinical manifestations they underlie. A detailed understanding of the functions of neurotransmitters and the consequences of their deficits can lead to rational drug design and treatment strategies appropriate for PD-D patients. In a wider context it is of interest to consider to what extent drugs that have some efficacy in people with Alzheimer’s disease (AD) might work better or worse in those with PD-D. This chapter will review neurochemical pathology in transmitter systems in PD-D and potential associations with clinical symptoms.
Information on neurotransmitter make-up and receptors is gleaned most excitingly and usefully, in terms of guiding therapy, from in vivo imaging, but it is obtained in greater detail and with information on several parameters together from post-mortem investigation.
The original finding of Hornykiewicz and Ehringer [1] of reduced dopamine concentration in post-mortem striatal tissue from PD cases (first reported in the early 1960s and republished in English in 1998 [2]), and its replacement therapy [3, 4] were revolutionary developments. Neurochemists have sought with hope to discover similar apparently simple relationships between other disorders or symptoms and single transmitter systems, but often find that combinations of neurotransmitter changes are responsible. PD-D by definition evolves from levodopa-responsive PD, but even PD is more than a disorder of movement and a deficiency of dopamine [5].
Changes in neurotransmitter systems in PD-D
Dopamine: pre-synaptic dopaminergic measures
As the disease progresses, concentrations of dopamine and homovanillic acid continue to decline and are consequently further reduced in PD-D than in PD. The loss of dopamine follows a pattern which reflects neuron loss in the substantia nigra [6], progressively affecting areas of low calbindin immunostaining first. The ratio of homovanillic acid to dopamine (each measured as pmol/mg protein) is an index of dopamine turnover, which is elevated in PD to an average of 45 times normal in the putamen but is not increased significantly over controls in dementia with Lewy bodies (DLB) [7]. Although this study from 1999 was not prospective, within the PD cases analysed those who had cognitive problems recorded in their case notes (n = 6) had lower homovanillic acid/dopamine ratios than those without (n = 9) (8 ± 6 versus 50 ± 44; two-tailed f-test, p = 0.04). Increased turnover is one of the compensatory changes that occurs in PD and begins to fail in PD-D.
Reduced dopamine concentration is mirrored by dopamine transporter (DAT) density. This has been measured both in vitro and in vivo in PD-D, and is reliably shown to be reduced below PD levels (and is also lower than in DLB). 2p-Carbomethoxy-3p-(4-iodophenyl)-N-(3-fluoropropyl)- N-nortropane (FP-CIT) single-photon emission computed tomography (SPECT) shows DAT density in PD-D to be reduced by more than 50% compared with DLB or PD [8].
Loss of substantia nigra and DAT may not initially be symmetrical between hemispheres, and this is reflected by unilateral expression of symptoms, especially rigidity [9, 10], although there is still significant bilateral loss. Evolution to PD-D shows a reduction of dopamine markers to a similar extent bilaterally [8].
Given the huge reduction in dopamine transmission in PD-D affecting extrastriatal areas (the thalamus, nucleus accumbens, and probably cortical areas which are more difficult to investigate) there are consequent effects on more than motor function. The thalamus receives dopamine via nigrostriatal collaterals, which have been shown to have depleted dopamine transporter immuno- reactivity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model of PD [11]. Nigrothalamic dopamine is likely to be reduced in PD-D. Using 125I-N-(3-iodoprop- (2E)-enyl)-2p-carbomethoxy-3p-(4,-methylphenyl)nortropane (PE2I) autoradiography, tracts from the substantia nigra bifurcating to course through both the globus pallidus and along the margin of the reticular nucleus of the thalamus can be visualized, and these tracts are at least 50% less dense in PD-D, DLB, and PD compared with controls. At these most posterior striatal levels, DAT were more extensively reduced in the caudate in PD-D than in PD and DLB, especially in the ventromedial section. At these caudal levels clinical correlations were, not surprisingly, with extrapyramidal symptoms, with greater reductions in the putamen and the tract along the reticular nucleus being associated with more severe Hoehn and Yahr stages and Unified Parkinson's Disease Rating Scale scores. Comparing PD-D to DLB with a similar severity of movement disability (Hoehn and Yahr stage 3 only) there was greater loss of DAT in the ventromedial puta- men and medial caudate in PD-D, perhaps showing some residual efficacy of compensatory mechanisms in PD (which are not invoked in DLB). A report using fluorodopa PET imaging also suggests that dopaminergic depletion in the caudate contributes to cognitive impairment in PD patients [12], and a study of progression of decline in DAT in PD-D, PD, and DLB showed correlation with cognitive decline [13].
