Preclinical (premotor) Parkinson's disease.

Parkinson's disease (PD) is an idiopathic disease caused by necrosis and apoptosis of dopaminergic cells in the brainstem, which are probably induced by oxidative stress. Current therapeutic strategies comprise symptomatic and restorative treatment. Neuroprotective treatment, however, is close to becoming reality. As neuroprotective therapy may be of particular benefit to the preclinical and/or very early PD patients, identifying patients in the early stages of the disease is a priority. Both [18F]dopa positron emission tomography (PET) and [123I]beta-CIT single photon emission computed tomography (SPECT) imaging may be useful tools in diagnosing early (preclinical) PD. As screening the whole population for preclinical PD is not realistic, one has to select subjects with a high risk for this disease. Olfactory disturbances, subtle neurocognitive dysfunction, visuomotor control abnormalities and, to a lesser degree, mood and personality disorders, have lately been suggested to precede or accompany early clinical motor hallmarks of PD. In an epidemiological study, 500 first-degree relatives of PD patients were assessed for these signs and symptoms, and [123I]beta-CIT SPECT was performed on patients in the top 10% and the bottom 10% with regard to sense of smell. In this report, the study design and initial data from this ongoing study will be presented.

Mental dysfunction in Parkinson's disease.

The pathological hallmark of Parkinson's disease (PD) is a degeneration of the dopamine (DA) producing cells in the substantia nigra and the ventral tegmentum, resulting in a dopamine deficiency in the dopaminergic projection areas with defective functioning of specific cortico-subcortical extrapyramidal circuits. Depending on which circuits (;motor', ;association' or ;limbic') are involved, and on the extent of the accompanying noradrenergic, serotonergic and cholinergic detrition in PD, dysfunction may result in motor deficits, mood disturbances or cognitive deficits, sometimes proceeding to dementia. Drug-induced psychosis occurs in approximately 15-20% of patients treated with dopaminergic agents. In PD, mainly nigrostriatal dopamine (A9) is depleted, leading to progressive motor dysfunction with subtle cognitive disturbances. As a rule, the neuropsychological deficit in PD might be described as the inability to switch cortical behavioral programmes in situations requiring the internal regulation of behavior. In daily life, in most patients these deficits do not become manifest, due to the abundance of external information to guide behavior. When the ability to use environmental information or external cues is lost as well, significant cell loss in the ventral tegmental area, with reduced DA-innervation of the mesocorticolimbic regions and the nucleus accumbens, must be suspected. This leads to clinically overt defects not only in the ;motor' but also in the ;limbic' and ;association' circuits. In addition to more severe cognitive disturbances or even dementia, this may also lead to mood disorders and drug-induced psychosis. Depression then occurs as the cortical modulation of limbic activity has become deficient, leading to emotional reactions disproportionate to the thoughts that evoke them. The proposed mechanism of psychosis in PD is that cortical sensory input is misinterpreted, leading to misperceptions (hallucinations) or false beliefs about reality due to a reduced ;signal-to-noise' ratio by insufficient processing of relevant information.

Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell.

By the time a clinical diagnosis of Parkinson's disease (PD) is made, a significant loss of dopaminergic neurons has already occurred. Identifying patients in the period between the presumed onset of dopaminergic cell loss and the appearance of clinical parkinsonism may be of major importance in the development of effective neuroprotective treatment strategies. In an effort to develop a feasible strategy to detect preclinical PD, a combination of olfactory processing tasks, including odor detection, odor identification, and odor discrimination was used to select groups of hyposmic and normosmic individuals from a total of 250 relatives (parents, siblings, or children) of subjects with PD. Single photon emission computed tomography (SPECT) with [123I]beta-CIT as a dopamine transporter ligand was used to assess nigrostriatal dopaminergic function in 25 hyposmic and 23 normosmic relatives of PD patients. An abnormal reduction in striatal dopamine transporter binding was found in 4 out of 25 hyposmic relatives of PD patients, two of whom subsequently developed clinical parkinsonism, and in none of the 23 normosmic relatives. These observations demonstrate that subclinical reductions in dopamine transporter binding can be detected in asymptomatic relatives of sporadic PD patients by means of [123I]beta-CIT and SPECT. The results further indicate that olfactory deficits may precede clinical motor signs in PD.