Functional imaging studies of dopamine system and cognition in normal aging and Parkinson's disease

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Abstract

Modern functional imaging methods, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), provide non-invasive, quantitative tools for the direct measurement of neurotransmitter function in the living human brain. The dopamine system has been of key interest; first, because it has a prominant role in several cognitive and motor processes, and secondly because the tracers currently available for the dopamine system enable an effective investigation of various pre, post- and intra-synaptic processes. Recent functional imaging findings indicate that certain cognitive deficits associated with both normal aging and Parkinson's disease are modulated by changes in the brain dopamine system. This review covers the literature related to age-associated phenomena in the dopamine system studied with in vivo imaging. In particular, the focus is on describing and discussing the relationships between aging, cognition and the dopaminergic system in healthy subjects and in patients with Parkinson's disease.

Introduction

Technical improvements in functional imaging techniques, particularly the large palette of available dopaminergic tracers for positron emission tomography (PET) and single photon emission computed tomography (SPECT), have enabled accurate measurements of complex pre-, post- and intra-synaptic dopaminergic phenomena in the living brain. For instance, it is currently possible to quantify dopaminergic function in cortical brain regions with very low dopamine activities, or actual fluctuations in the concentration of endogenous dopamine in synapses of living human subjects. Neurons, including those in the three dopaminergic pathways, are, as post-mitotic cells, particularly vulnerable to age-associated degeneration. In Parkinson's disease, an adult onset progressive disorder of the extrapyramidal motor system, the function of these dopaminergic pathways is severely compromised. Parkinson's disease has a classical symptom triad of resting tremor, bradykinesia and rigidity. In addition, patients often have balance problems, autonomic nervous system dysfunction and they show cognitive and psychiatric (especially depressive) features. Pathologically, the hallmark of Parkinson's disease is the progressive loss of pigmented dopaminergic neurons in the substantia nigra (and other brain stem nuclei). This neuronal loss leads to the fundamental biochemical deficit which is a deficiency of dopamine in the striatum, especially in the putamen. Later in the disease course, the dopaminergic deficiency becomes evident also in other brain areas. The severity of hypokinesia and rigidity in Parkinson's disease has been repeatedly shown to be related to both nigral neuronal loss and striatal dopamine deficiency.

PET and SPECT are non-invasive nuclear medicine techniques that utilise radiopharmaceuticals and a tomographic instrument to provide quantitative cross-sectional images. Both methods are firmly established as important scientific and clinical research tools. The successful use of these methods in brain research requires great care due to several potential technical confounding factors, such as limitations in scanner resolution and sensitivity, attenuation, scatter, partial volume effect, accidental coincidences and dead time. In addition, the affinity and selectivity of the radioligands used are important factors determining the possibilities to visualize neuronal function or receptors, for instance in areas of low terminal or receptor concentration. Bearing in mind the versatility of dopaminergic PET and SPECT, it is not surprising that both the normal age-associated degeneration of the dopamine system and the abnormal degeneration of the same system in Parkinson's disease have drawn much attention in functional imaging studies. Importantly, with the combination of behavioral tests and in vivo imaging, intriguing findings have recently been made about the functional significance of the age- and disease-associated dopaminergic degeneration in cognitive and motor processes. In the present review, we discuss and draw some preliminary conclusions about the links between aging, dopamine and cognition in the healthy brain and in the brain affected by Parkinson's disease.

Section snippets

Loss of dopaminergic function in normal aging

In humans, the age-dependent decline of brain dopamine levels was first demonstrated in the basal ganglia post-mortem [8], and soon after, the imaging of the living dopamine system became possible [21]. PET and SPECT studies have mostly confirmed the age-related dopaminergic loss seen post-mortem, particularly with tracers specific for dopamine receptors or transporters.

The interneuronal communication in the dopaminergic pathways is achieved by dopamine which interacts specifically with its

Cognition and dopaminergic function in normal aging

Imaging studies demonstrating relationships between cognition and dopamine are summarized in Table 1. As discussed earlier, the age-dependent decline of dopamine D2-like receptor availability has been well documented. Volkow and colleagues [64] extended the PET investigations to behavior and showed that the age reductions in D2-like receptor availability of the caudate nucleus are associated with impairments in both motor and cognitive functions. Although the strongest association was seen with

Cognitive and motor dysfunction in Parkinson's disease

The cognitive changes most often associated with Parkinson's disease are executive dysfunction, memory and visuospatial impairments. Because frontal lobe type deficits predominate, cognitive impairment in Parkinson's disease has been said to be a progressive dysexecutive syndrome [12]. Executive functions consist in broad terms of the ability to plan, organize and regulate goal-directed behavior. Central elements of executive functions include working memory and attention. These processes are

Cognition and dopaminergic function in Parkinson's disease

Both rats and monkeys with lesioning of nigral neurons or dopamine depletion in the frontal cortex or in the caudate nucleus have shown behavioral deficits resembling frontal lobe dysfunction [59], [36], and these impairments in cognitive functions have been ameliorated with dopamine agonists [40], [60]. In agreement with the animal data, dopamine also seems to be involved in cognitive symptoms in Parkinson's disease patients.

A model of anatomically and functionally segregated

Conclusions and future directions

Parkinson's disease is a severe extrapyramidal syndrome of the dopamine system but, even in the normal elderly, mild parkinsonian-like extrapyramidal symptoms are common [47]. Although aging and Parkinson's disease might share certain mechanisms in the dopamine system, the level of biochemical, motor and cognitive degeneration is more severe in Parkinson's disease both at qualitative and quantitative level. Some imaging studies have indicated that, although the dopaminergic degeneration, for

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