Erik Ch. Wolters

Idiopathic hyposmia as a preclinical sign of Parkinson's disease

Olfactory dysfunction is an early and common symptom in Parkinsons disease (PD). In an effort to determine whether otherwise unexplained (idiopathic) olfactory dysfunction is associated with an increased risk of developing PD, we designed a prospective study in a cohort of 361 asymptomatic relatives (parents, siblings, or children) of PD patients. A combination of olfactory detection, identification, and discrimination tasks was used to select groups of hyposmic (n = 40) and normosmic (n = 38) individuals for a 2‐year clinical follow‐up evaluation and sequential single‐photon emission computed tomography (SPECT), using [123I]β‐CIT as a dopamine transporter ligand, to assess nigrostriatal dopaminergic function at baseline and 2 years from baseline. A validated questionnaire, sensitive to the presence of parkinsonism, was used in the follow‐up of the remaining 283 relatives. Two years from baseline, 10% of the individuals with idiopathic hyposmia, who also had strongly reduced [123I]β‐CIT binding at baseline, had developed clinical PD as opposed to none of the other relatives in the cohort. In the remaining nonparkinsonian hyposmic relatives, the average rate of decline in dopamine transporter binding was significantly higher than in the normosmic relatives. These results indicate that idiopathic olfactory dysfunction is associated with an increased risk of developing PD of at least 10%. Ann Neurol 2004

[123I]FP-CIT SPECT shows a pronounced decline of striatal dopamine transporter labelling in early and advanced Parkinson's disease.

OBJECTIVES: The main neuropathological feature in Parkinsons disease is a severe degeneration of the dopaminergic neurons in the substantia nigra resulting in a loss of dopamine (DA) transporters in the striatum. [123I]beta-CIT single photon emission computed tomography (SPECT) studies have demonstrated this loss of striatal DA transporter content in Parkinsons disease in vivo. However, studies with this radioligand also showed that an adequate imaging of the striatal DA transporter content could only be performed on the day after the injection of radioligand, which is not convenient for outpatient evaluations. Recently, a new radioligand [123I]FP-CIT, with faster kinetics than beta-CIT, became available for imaging of the DA transporter with SPECT, and the applicability of this ligand was tested in patients with early and advanced Parkinsons disease, using a one day protocol. METHODS: [123I]FP-CIT SPECT was performed in six patients with early and 12 patients with advanced Parkinsons disease, and in six age matched healthy volunteers. RESULTS: Compared with an age matched control group striatal [123I]FP-CIT uptake in patients with Parkinsons disease was decreased, and this result was measurable three hours after injection of the radioligand. In the Parkinsons disease group the uptake in the putamen was reduced more than in the caudate nucleus. The contralateral striatal uptake of [123I]FP-CIT was significantly lower than the ipsilateral striatal uptake in the Parkinsons disease group. Specific to non-specific striatal uptake ratios correlated with the Hoehn and Yahr stage. A subgroup of patients with early Parkinsons disease also showed significantly lower uptake in the putamen and lower putamen:caudate ratios than controls. CONCLUSION: [123I]FP-CIT SPECT allows a significant discrimination between patients with Parkinsons disease and age matched controls with a one day protocol, which will be to great advantage in outpatient evaluations.

Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study

Dopamine agonists are used as initial treatment in patients with Parkinsons disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long‐term studies, allowing “rescue” therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide‐versus‐L‐dopa‐monotherapy‐and‐positron‐emission‐tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa “rescue” medication. This multicenter, double‐blind, randomized, 3‐year trial compared pergolide monotherapy (n = 148) with levodopa monotherapy (n = 146) in dopamine‐naive patients with early PD (Hoehn and Yahr stage 1–2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinsons Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.

Long‐term benefits of rivastigmine in dementia associated with Parkinson's disease: An active treatment extension study

In patients with dementia associated with Parkinsons disease (PD), the efficacy and safety of rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, were previously demonstrated in a 24‐week double‐blind placebo‐controlled trial. Our objective was to determine whether benefits were sustained over the long term. Following the double‐blind trial, all patients were permitted to enter an active treatment extension study, during which they received rivastigmine 3–12 mg/day. Standard safety assessments were performed. Efficacy assessments included the Alzheimers Disease Assessment Scale cognitive subscale (ADAS‐cog) and other measures of cognition, daily function, neuropsychiatric symptoms, and executive function. Of 433 patients who completed the double‐blind trial, 334 entered and 273 completed the active treatment extension. At 48 weeks, the mean ADAS‐cog score for the whole group improved by 2 points above baseline. Placebo patients switching to rivastigmine for the active treatment extension experienced a mean cognitive improvement similar to that of the original rivastigmine group during the double‐blind trial. The adverse event profile was comparable to that seen in the double‐blind trial. Long‐term rivastigmine treatment appeared well tolerated and may provide sustained benefits in dementia associated with PD patients who remain on treatment for up to 48 weeks.

[(123)I]beta-CIT SPECT is a useful method for monitoring dopaminergic degeneration in early stage Parkinson's disease

Objectives:To examine the validity of [123I]β-CIT SPECT for monitoring the progression of dopaminergic degeneration in Parkinson’s disease; to investigate the influence of short term treatment with D2receptor agonists on striatal [123I]β-CIT binding; and to determine the sample size and frequency of SPECT imaging required to demonstrate a significant effect of a putative neuroprotective agent. Methods:A group of 50 early stage Parkinson’s disease patients was examined. Two SPECT imaging series were obtained, 12 months apart. The mean annual change in the ratio of specific to non-specific [123I]β-CIT binding to the striatum, putamen, and caudate nucleus was used as the outcome measure. Results:A decrease in [123I]β-CIT binding ratios between the two images was found in all regions of interest. The average decrease in [123I]β-CIT binding ratios was about 8% in the whole striatum, 8% in the putaminal region, and 4% in the caudate region. Comparison of scans done in nine patients under two different conditions—in the off state and while on drug treatment—showed no significant alterations in the expression of striatal dopamine transporters as measured using [123I]β-CIT SPECT. Power analysis indicated that to detect a significant (p < 0.05) effect of a neuroprotective agent with 0.80 power and 30% of predicted protection within two years, 216 patients are required in each group when the effects are measured in the whole putamen. Conclusions:[123I]β-CIT SPECT seems to be a useful tool to investigate the progression of dopaminergic degeneration in Parkinson’s disease and may provide an objective method of measuring the effectiveness of neuroprotective treatments. Short term treatment with a D2agonist does not have a significant influence on [123I]β-CIT binding to dopamine transporters. If the latter finding is replicated in larger groups of patients, it supports the suitability of [123I]β-CIT SPECT for examining the progression of neurodegeneration in patients being treated with D2receptor agonists.

Hyposmia and Executive Dysfunction as Predictors of Future Parkinson's Disease: A Prospective Study

Olfactory deficits and executive dysfunction are early and common symptoms in Parkinsons disease (PD). Previous studies have shown that hyposmia can be a first sign of PD. The aim of the present study was to determine which of three olfactory tests and two selected tests of executive function would be the best predictor of future PD over a 5 year period. In a cohort of 361 nonparkinsonian, nondemented first‐degree relatives of PD patients, in whom alternative causes of olfactory dysfunction were excluded, we measured baseline performance on three olfactory and two executive function tasks. Five years from baseline, clinical neurological evaluation and/or a screening questionnaire, sensitive to the presence of Parkinsonism, were used to detect individuals developing clinical PD. Our results show that in first degree relatives of PD patients worse performance on each of three olfactory processing tasks was associated with an increased risk of developing PD within 5 years, whereas performance on selected tests of executive dysfunction was not associated with an increased risk of developing PD. Interestingly, impaired odor discrimination was the best predictor for future PD.

Management of non-motor symptoms in advanced Parkinson disease

Progress in pharmacology has markedly improved the treatment of early Parkinsons disease. The management of advanced Parkinsons symptoms, however, remains a challenge. These symptoms are divided into motor and non-motor symptoms. Non-motor symptoms may appear early or late in the disease and sometimes even before the onset of the first motor symptoms confirming the diagnosis. The spectrum of non-motor symptoms encompasses autonomic dysfunctions, sleep disorders, mood disorders, impulse control disorders, cognitive dysfunction, dementia, paranoia and hallucinations. They are often less appreciated than motor symptoms but are important sources of disability for many PD patients. This review describes these non-motor symptoms and their managements.

Non-motor extranigral signs and symptoms in Parkinson's disease

Clinical symptoms in Parkinsons disease (PD) comprise both motor and non-motor symptoms. In this disease, synucleinopathic-induced, nigral dopamine deficiency-related dysfunction of the basal ganglia is held responsible for the characteristic levodopa-responsive motor signs and symptoms (bradykinesia, hypokinesia, rigidity), known as parkinsonism and essential for clinical diagnosis in PD, as well as subtle motivational and cognitive dysfunctions. Some motor symptoms, such as tremor and postural instability, and most non-motor symptoms, however, are not fully levodopa-responsive, and suggested to manifest extranigral pathology. These symptoms include autonomic, sleep, sensory and neuropsychiatric symptoms, which in some cases may precede the first signs of motor parkinsonism, closely correlating with the progression of Lewy body pathology in PD. The recognition and treatment of these mostly under-recognized and under-treated symptoms is important, as these symptoms might have more impact on the quality of life in PD patients as compared to motor parkinsonism. On top of this, recognition of these manifestations in the prodromal phase of motor PD is critical to early diagnosis and treatment, as disease-modifying drugs, once identified, should be initiated as soon as possible, preferably in this premotor phase of the disease. On top of this, (non)motor extranigral symptoms in PD might also be of iatrogenic origin, whether directly as indirectly. During conventional, oral, dopaminomimetic treatment, the progressive loss of striatal dopaminergic nerve endings with the loss of cerebral dopamine storage capacity, renders the cerebral dopamine level fully dependent of the plasma levodopa levels, thus changing dopaminergic receptor stimulation from continuous to a more pulsatile pattern. Supposedly due to this process, neuroplastic changes in (sub)cortical dopaminergic pathways might cause therapeutic response fluctuations: motor and nonmotor fluctuations with anxiety- and panic-attacks and/or mood swings, dyskinesias and punding. Finally, dopaminomimetic pharmacotherapy may also induce extranigral non-motor drug-related direct adverse effects, such as impulse control disorders. In this article, non-motor signs and symptoms of extranigral PD-related pathology will be discussed, as well as the (suggested) criteria for diagnosis and treatment. Of course, also the recognition of the signs and symptoms of the prodromal (premotor) phase, suggestive for the presence of the PD, will be discussed. Iatrogenic non-motor symptoms, though, will not be further discussed.

Frontal–striatal abnormalities underlying behaviours in the compulsive–impulsive spectrum

In this paper, we tentatively bring together the psychiatric, neurological and addiction perspectives on the impulsive-compulsive spectrum of neuropsychiatric disorders, in order to understand the pathophysiology of impulse control disorders (ICDs) in Parkinsons disease. In an attempt to try to pool the various levels of information we will therefore focus on three disorders within the impulse-compulsive spectrum, i.e., obsessive-compulsive disorder (OCD), ICDs in Parkinsons disease, and cocaine seeking behaviour. Whereas there are large differences between these three domains, each with their own nomenclature, hypotheses and study results, they share the focus on an imbalance within and between the frontal-striatal circuits as underlying substrate for the behaviours. For each disorder, we summarize the results from recent studies in order to describe in which way alterations in the frontal-striatal circuits contribute to the phenotype. The phenomenological overlap between ICDs in Parkinsons disease, addiction and OCD needs further investigation, since better understanding of the overlapping and differentiating characteristics will contribute to our understanding of the pathophysiology of the disturbances and treatment alternatives.

Variability in the clinical expression of Parkinson's disease

Parkinsonism is a clinical syndrome characterized by bradykinesia, hypo-/akinesia, muscular rigidity, and resting tremor, mainly caused by Parkinsons disease (PD). Symptoms of PD are due to a progressive loss of nigral neurons causing striatal dopaminergic denervation. However, nigral degeneration is only a part of the underlying synucleinopathy, and clinical symptoms go far beyond motor parkinsonism. Olfactory disturbances, fatigue, pain, autonomic dysfunction, sleep fragmentation, depression, and dementia with or without psychosis are frequently seen. The variability in the expression of these signs and symptoms, as discussed in this paper, might be explained by the specific topographical sequence of the pathology, depending on the extent and progression of the degenerative process at defined sites. Better insight in the clinicopathological correlations of this disease may help to further develop early diagnosis and adequate therapeutic strategies.