Side of symptom onset affects motor dysfunction in Parkinson's disease.

The healthy brain appears to have an asymmetric dopamine distribution, with higher levels of dopamine in the left than in the right striatum. Here, we test the hypothesis that this neurochemical asymmetry renders the right striatum relatively more vulnerable to the effects of dopaminergic denervation in Parkinson's disease (PD). Using the pegboard dexterity test, we compared motor performance of both hands between healthy subjects (n=48), PD patients with predominantly right-hemispheric dopamine depletion (PD-RIGHT; n=83) and PD patients with more severe left-hemispheric dopamine depletion (PD-LEFT; n=103). All subjects were right-handed. After adjusting for hand-dominance effects, we found that PD-RIGHT patients exhibited a 55% larger difference between right and left dexterity scores than PD-LEFT patients. This effect could be attributed to greater motor dysfunction of the more-affected hand in PD-RIGHT patients, while the less-affected hand performed similarly in both groups. We conclude that the side of symptom onset affects motor dysfunction in PD, and suggest that the non-dominant right hemisphere may be more susceptible to dopaminergic denervation than the dominant left hemisphere.

FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome.

BACKGROUND: The combination of early-onset, progressive parkinsonism with pyramidal tract signs has been known as pallido-pyramidal or parkinsonian-pyramidal syndrome since the first description by Davison in 1954. Very recently, a locus was mapped in a single family with an overlapping phenotype, and an FBXO7 gene mutation was nominated as the likely disease cause. METHODS: We performed clinical and genetic studies in two families with early-onset, progressive parkinsonism and pyramidal tract signs. RESULTS: An FBXO7 homozygous truncating mutation (Arg498Stop) was found in an Italian family, while compound heterozygous mutations (a splice-site IVS7 + 1G/T mutation and a missense Thr22Met mutation) were present in a Dutch family. We also found evidence of expression of novel normal splice-variants of FBXO7. The phenotype associated with FBXO7 mutations consisted of early-onset, progressive parkinsonism and pyramidal tract signs, thereby matching clinically the pallido-pyramidal syndrome of Davison. The parkinsonism exhibits varying degrees of levodopa responsiveness in different patients. CONCLUSIONS: We conclusively show that recessive FBXO7 mutations cause progressive neurodegeneration with extrapyramidal and pyramidal system involvement, delineating a novel genetically defined entity that we propose to designate as PARK15. Understanding how FBXO7 mutations cause disease will shed further light on the molecular mechanisms of neurodegeneration, with potential implications also for more common forms of parkinsonism, such as Parkinson disease and multiple system atrophy.

ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease.

OBJECTIVE: To assess the prevalence, nature, and associated phenotypes of ATP13A2 gene mutations among patients with juvenile parkinsonism (onset <21 years) or young onset (between 21 and 40 years) Parkinson disease (YOPD). METHODS: We studied 46 patients, mostly from Italy or Brazil, including 11 with juvenile parkinsonism and 35 with YOPD. Thirty-three cases were sporadic and 13 had positive family history compatible with autosomal recessive inheritance. Forty-two had only parkinsonian signs, while four (all juvenile-onset) had multisystemic involvement. The whole ATP13A2 coding region (29 exons) and exon-intron boundaries were sequenced from genomic DNA. RESULTS: A novel homozygous missense mutation (Gly504Arg) was identified in one sporadic case from Brazil with juvenile parkinsonism. This patient had symptoms onset at age 12, levodopa-responsive severe akinetic-rigid parkinsonism, levodopa-induced motor fluctuations and dyskinesias, severe visual hallucinations, and supranuclear vertical gaze paresis, but no pyramidal deficit nor dementia. Brain CT scan showed moderate diffuse atrophy. Furthermore, two Italian cases with YOPD without atypical features carried a novel missense mutation (Thr12Met, Gly533Arg) in single heterozygous state. CONCLUSIONS: We confirm that ATP13A2 homozygous mutations are associated with human parkinsonism, and expand the associated genotypic and clinical spectrum, by describing a homozygous missense mutation in this gene in a patient with a phenotype milder than that initially associated with ATP13A2 mutations (Kufor-Rakeb syndrome). Our data also suggest that ATP13A2 single heterozygous mutations might be etiologically relevant for patients with YOPD and further studies of this gene in Parkinson disease are warranted.

Diagnostic value of asymmetric striatal D2 receptor upregulation in Parkinson's disease: an [123I]IBZM and [123I]FP-CIT SPECT study.

INTRODUCTION: Striatal postsynaptic D2 receptors in Parkinson's disease (PD) are thought to be upregulated in the first years of the disease, especially contralateral to the clinically most affected side. The aim of this study was to evaluate whether the highest striatal D2 binding is found contralateral to the most affected side in PD, and whether this upregulation can be used as a diagnostic tool. METHODS: Cross-sectional survey was undertaken of 81 patients with clinically asymmetric PD, without antiparkinsonian drugs and with a disease duration of < or = 5 years and 26 age-matched controls. Striatal D2 binding was assessed with [123I]IBZM SPECT, and severity of the presynaptic dopaminergic lesion with [123I]FP-CIT SPECT. RESULTS: The mean striato-occipital ratio of [123I]IBZM binding was significantly higher in PD patients (1.56 +/-0.09) than in controls (1.53 +/-0.06). In PD patients, higher values were found contralateral to the clinically most affected side (1.57 +/-0.09 vs 1.55 +/-0.10 ipsilaterally), suggesting D2 receptor upregulation, and the reverse was seen using [123I]FP-CIT SPECT. However, on an individual basis only 56% of PD patients showed this upregulation. CONCLUSION: Our study confirms asymmetric D2 receptor upregulation in PD. However, the sensitivity of contralateral higher striatal [123I]IBZM binding is only 56%. Therefore, the presence of contralateral higher striatal IBZM binding has insufficient diagnostic accuracy for PD, and PD cannot be excluded in patients with parkinsonism and no contralateral upregulation of D2 receptors, assessed with [123I]IBZM SPECT.

Startle responses in Parkinson patients during human gait.

Falls frequently occur in patients with Parkinson's disease (Bloem et al. 2001). One potential source for such falls during walking might be caused by the reaction to loud noises. In normal subjects startle reactions are well integrated in the locomotor activity (Nieuwenhuijzen et al. 2000), but whether this is also achieved in Parkinson patients is unknown. Therefore, in the present study, the startle response during walking was studied in eight patients with Parkinson's disease and in eight healthy subjects. To examine how startle reactions are incorporated in an ongoing gait pattern of these patients, unexpected auditory stimuli were presented in six phases of the step cycle during walking on a treadmill. For both legs electromyographic activity was recorded from biceps femoris and tibialis anterior. In addition, we measured the stance and swing phases of both legs, along with the knee angles of both legs and the left ankle angle. In all subjects and all muscles, responses were detected. The pattern of the responses, latency, duration, and phase-dependent modulation was similar in both groups. However, the mean response amplitude was larger in patients due to a smaller habituation rate. No correlation was found between the degree of habituation and disease severity. Moreover, a decreased habituation was already observed in mildly affected patients, indicating that habituation of the startle response is a sensitive measure of Parkinson's disease. The results complement the earlier findings of reduced habituation of blink responses in Parkinson's disease. With respect to behavioral changes in healthy subjects we observed that startle stimuli induced a shortening of the step cycle and a decrease in range of motion. In the patient group, less shortening of the subsequent step cycle and no decrease in range of motion of the knee and ankle was seen. It is argued that the observed changes might contribute to the high incidence of falls in patients with Parkinson's disease.

Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes.

OBJECTIVE: To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism. METHODS: The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases. RESULTS: Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later. CONCLUSIONS: PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.

New parkin mutations and atypical phenotypes in families with autosomal recessive parkinsonism.

The frequency of parkin mutations was evaluated in 30 families of highly diverse geographic origin with early-onset autosomal recessive parkinsonism. Twelve different mutations, six of which were new, were found in 10 families from Europe and Brazil. Patients with parkin mutations had significantly longer disease duration than patients without the mutation but with similar severity of disease, suggesting a slower disease course. Two patients with parkin mutations had atypical clinical presentation at onset, with predominant tremor when standing.

[Dementia with Lewy bodies; 2 patients with exacerbation due to an atypical antipsychotic, but with a favorable response to the cholinesterase inhibitor rivastigmine]. / Dementie met Lewy-lichaampjes; 2 patiënten met verergering door een atypisch antipsychoticum, maar met een gunstige reactie op de cholinesteraseremmer rivastigmine.

In two patients, men aged 80 and 75 years with cognitive deterioration, hallucinations and parkinsonism, the clinical diagnosis 'dementia with Lewy bodies' was established. Treatment with an atypical antipsychotic, risperidone and olanzapine respectively, resulted in an exacerbation of the parkinsonism. Rivastigmine evidently improved the psychosis, the anxiety and the cognitive, mood and behaviour disorders. Titrated treatment with levodopa improved the mobility without an increase of the psychosis. The treatment of dementia with Lewy bodies is complex. Levodopa can lead to an increase in visual hallucinations. Antipsychotics often cause serious side effects, such as increasing parkinsonism, sedation and cognitive deterioration. Cholinesterase inhibitors such as rivastigmine could possibly provide an alternative treatment for the neuropsychiatric symptoms.

Improvement of voicing in patients with Parkinson's disease by speech therapy.

Speech therapy in PD patients, focusing on an increase of phonatory-respiratory effort, has adverse effects because it raises vocal pitch and laryngeal muscle tension. The authors' approach, the Pitch Limiting Voice Treatment (PLVT), increases loudness but at the same time sets vocal pitch at a better level. In this study, the Lee Silverman Voice Treatment ("think loud, think shout") and PLVT ("speak loud and low") are compared. Both treatments produce the same increase in loudness, but PLVT limits an increase in vocal pitch and prevents a strained or pressed voicing.

Stimulation of growth-hormone release with clonidine does not distinguish individual cases of idiopathic Parkinson's disease from those with striatonigral degeneration.

Multiple System Atrophy (MSA) and idiopathic Parkinson's disease (PD) can be difficult to distinguish. There is an ongoing debate about the diagnostic value of the growth-hormone response to clonidine (CGH-test) in PD and MSA. We investigated whether the CGH-test can identify individual patients in the early stages of PD (n = 21) and Striatonigral Degeneration (SND, n = 11), a particular variety of MSA. Patients were diagnosed on the basis of clinical criteria and IBZM-SPECT. Clonidine induced a greater total serum growth-hormone production in PD than in SND (p = 0.01). However, taking the difference in prevalence of PD and SND into account, and because of the low likelihood ratios of the test, an increase of GH after clonidine increases the pre-test probability for PD by about only 5 %, while an absent response of GH also increases the pre-test probability for SND by about 5 %. We conclude that the CGH-test discriminates between groups of patients with PD and SND, but has little practical diagnostic value for identifying individual patients.

Intermediate CAG repeat lengths (53,54) for MJD/SCA3 are associated with an abnormal phenotype.

We report on a Dutch family in which 4 members in 2 generations have intermediate repeat lengths (53 and 54) for Machado-Joseph Disease/Spinocerebellar Ataxia (MJD/SCA3). All but the youngest have a restless legs syndrome with fasciculations and a sensorimotor axonal polyneuropathy. Central neurological abnormalities are only present in 2. This family shows that intermediate repeat lengths can be pathogenic and may predispose for restless legs and peripheral nerve disorder.

The clinical benefit of imaging striatal dopamine transporters with [123I]FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism.

[123I]FP-CIT (N-omega-fluoropropyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl)nortropane) has been developed successfully as a radioligand for single-photon emission tomography (SPET) imaging of dopamine transporters, which are situated in the membrane of dopaminergic neurons. Imaging of these transporters has shown promise as a clinical tool to detect degeneration of the dopaminergic nigrostriatal pathway. Several "presynaptic parkinsonian" syndromes, such as Parkinson's disease or multiple system atrophy, are characterised by degeneration of the nigrostriatal pathway. [123I]FP-CIT SPET imaging studies have shown the ability to detect loss of striatal dopamine transporters in such syndromes. However, in clinical practice it is sometimes difficult, but important, to discriminate patients with "presynaptic parkinsonism" from those with other forms of parkinsonism not characterised by loss of presynaptic dopaminergic cells (e.g. psychogenic parkinsonism or drug-induced postsynaptic parkinsonism). In these inconclusive cases, it may be of value to confirm or exclude the existence of degeneration of nigrostriatal dopaminergic cells by using imaging techniques such as [123I]FP-CIT SPET. Using [123I]FP-CIT SPET, we have imaged the striatal dopamine transporters in a group of patients with inconclusive forms of parkinsonism, and, moreover, have been able to perform clinical follow-up of these patients 2-4 years after imaging. In 33 inconclusive cases, ratios of specific to non-specific binding were calculated for the caudate nucleus and putamen following [123I]FP-CIT SPET imaging and compared with ratios obtained in healthy controls. In nine of the patients, degeneration of the nigrostriatal pathway was found scintigraphically and in all these cases, presynaptic parkinsonism was confirmed by clinical follow-up. In the other 24 subjects no degeneration was found scintigraphically. Forms of parkinsonism other than the presynaptic were confirmed at follow-up in 19 cases, and in three cases no conclusive diagnosis was established, but presynaptic parkinsonism was excluded clinically. A clinical diagnosis of presynaptic parkinsonism was established in two cases: one case of multiple system atrophy (in this patient loss of dopamine D2 receptors was found with [123I]iodobenzamide SPET performed 2 weeks after [123I]FP-CIT imaging) and one case of Parkinson's disease. Our data suggest that the positive predictive value of [123I]FP-CIT imaging is very high, and although the negative predictive value is lower, dopamine transporter imaging offers the prospect of a quick, objective method to confirm or exclude presynaptic parkinsonism in inconclusive cases.

Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations.

A Dutch family with autosomal recessive early-onset parkinsonism showed a heterozygous missense mutation in combination with a heterozygous exon deletion in the parkin gene. Although the main clinical syndrome consisted of parkinsonism, the proband clinically had additional mild gait ataxia and pathologically showed neuronal loss in parts of the spinocerebellar system, in addition to selective loss of dopaminergic neurons in the substantia nigra pars compacta. Lewy bodies and neurofibrillary tangles were absent, but tau pathology was found.

Detection and assessment of the severity of levodopa-induced dyskinesia in patients with Parkinson's disease by neural networks.

Levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) have remained a clinical challenge. We evaluated the feasibility of neural networks to detect LID and to quantify their severity in 16 patients with PD at rest and during various activities of daily living. The movements of the patients were measured using four pairs of accelerometers mounted on the wrist, upper arm, trunk, and leg on the most affected side. Using parameters obtained from the accelerometer signals, neural networks were trained to detect and to classify LID corresponding to the modified Abnormal Involuntary Movement Scale. Important parameters for classification appeared to be the mean segment velocity and the cross-correlation between accelerometers on the arm, trunk, and leg. Neural networks were able to distinguish voluntary movements from LID and to assess the severity of LID in various activities. Based on the results in this study, we conclude that neural networks are a valid and reliable method to detect and to assess the severity of LID corresponding to the modified Abnormal Involuntary Movement Scale.

Decreased striatal dopamine D2 receptor binding in amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA): D2 receptor down-regulation versus striatal cell degeneration.

Recently, decreased striatal dopamine D2-receptor binding was demonstrated in vivo in amyotrophic lateral sclerosis (ALS). To further elucidate the pathogenetic mechanism underlying this D2-receptor deficit, a multi-level comparison was made between 30 sporadic ALS subjects and 24 patients with multiple system atrophy (MSA), a disorder clinically characterized by bradykinesia, neuroradiologically by severe D2-receptor loss, and neuropathologically by degenerating striatal cells. The extent of D2-deficit in ALS and MSA were within the same range, but extrapyramidal signs and symptoms were virtually absent in our ALS patients. Striatal cell loss in general or competitive D2-receptor occupancy could be considered unlikely in ALS. The striatum receives massive glutamatergic input and the pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. As other mechanisms (cell loss, receptor occupancy) could be ruled out, and as animal studies suggest that (excess of) glutamate decreases striatal D2-receptor synthesis, the striatal D2-receptor deficit in ALS is most likely to be caused by a receptor down-regulation.

Redundant-signals effects on reaction time, response force, and movement-related potentials in Parkinson's disease.

Studies using transcranial magnetic stimulation have established that patients with Parkinson's disease have increased motor cortex excitability. Relying on current evidence that the redundant-signals effect has its source in the motor system, we investigated whether, as a result of cortical hyperexcitability, Parkinson's disease patients demonstrate an enhancement of this effect. Eight patients with moderately severe Parkinson's disease and nine healthy control subjects participated in a task requiring simple manual responses to visual, auditory, and combined auditory-visual signals. During the task, motor cortex activation was recorded by means of movement-related EEG potentials, while responses were measured via isometric force recordings. The movement-related potentials and the force measures both yielded support for the view that the redundant-signals effect is partially caused in the motor system. However, the facilitatory effect of bimodal as compared to unimodal stimulation (i.e. the redundant-signals effect) was of the same size in Parkinson's disease patients and control subjects, as expressed in latency measures of the movement-related potentials and the force signals. We conclude that the redundant-signals effect is not enhanced in Parkinson's disease and that the mechanisms underlying this effect are probably not influenced by the increased motor cortex excitability found in this disease.

Relationship between memory strategies and motor symptoms in Parkinson's disease.

Patients with Parkinson's disease(PD) show a serious decrease in performance on tasks which lack explicit guidelines and which necessitate the subject to develop his or her own strategy. Using the California Verbal Learning Task(CVLT) we have found evidence that this phenomenon becomes also manifest in learning and memory. The goal of the present study on PD was to investigate whether or not there is an intrinsic relationship between PD-specific deviant learning characteristics and the severity of motor symptomatology. The results show, as expected, a significant correlation between the severity of bradykinetic/hypokinetic symptoms and the serial clustering gradient of the CVLT: the more bradykinetic PD patients (n = 48) were, the more they were dependent on the externally guided serial learning strategy. The findings are discussed in the context of our hypothesis that the actual deficit in patients with PD is a deficient processing of ambiguous internal cues.

Donders' law in torticollis.

We investigated head movements of patients with spasmodic torticollis toward targets in various directions. These patients, whose severe dystonia was reflected in an abnormal resting head position, appeared to retain a Donders'-type strategy for the control of the rotational degrees of freedom of the head. As in normals, rotation vectors, representing head orientation, were confined to a curved surface, which specifies how head torsion depends on gaze direction. The orientation of the surface in body coordinates, which was very stereotyped in normals, was different for patients. The same Donders surface was found for head movements and for stationary head postures, indicating that the same neural mechanism governs its implementation in both tasks. To interpret our results, we propose a conceptual scheme incorporating the basal ganglia, which are thought to be involved in the etiology of torticollis, and an implementation stage for Donders' law.